Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same

ABSTRACT

Beta-lapachone, which is poorly soluble in most pharmaceutically acceptable solvents, has demonstrated significant antineoplastic activity against human cancer lines. The present invention overcomes this significant limitation by teaching novel pharmaceutical compositions comprising a therapeutically effective amount of Beta-lapachone, or a derivative or analog thereof, and a pharmaceutically acceptable solubilizing carrier molecule, which may be at water-solubilizing carrier molecule such as hydroxypropyl-β-cyclodextrin, or an oil-based solubilizing carrier molecule, for enhancing the solubility of Beta-lapachone in aqueous solution. The therapeutically effective amount of Beta-lapachone, or a derivative or analog thereof, may be complexed with the pharmaceutically acceptable solubilizing carrier molecule in aqueous solution. The novel pharmaceutical compositions may be administered with a second anticancer agent or in combination with radiation therapy. A formulation of Beta-lapachone or a derivative or analog thereof, complexed with a pharmaceutically acceptable solubilizing carrier molecule, wherein the complex can be freeze-dried and when subsequently reconstituted in aqueous solution is substantially soluble is also disclosed. Emulsions of Beta-Lapachone in a pharmaceutically acceptable fat emulsion vehicle are also provided. Also disclosed are methods for treating cancer by administering to a patient the novel pharmaceutical compositions and formulations. Pharmaceutical kits are also provided.

FIELD OF THE INVENTION

[0001] The present invention is directed to pharmaceutical compositionsand formulations, as well as methods of administering thesepharmaceutical compositions and formulations, which comprise β-lapachone(Beta-lapachone), or a derivative or analog thereof, complexed orcombined with a solubilizing carrier molecule for enhancing thesolubility of β-lapachone in different solvent systems.

BACKGROUND OF THE INVENTION

[0002] Over 1.22 million new cancer cases will be diagnosed in the U.S.in the year 2001 alone. With more than 563,000 deaths annually, canceris the second leading cause of death behind heart disease (UBS Warburg“Disease Dynamics: The Cancer Market”, Nov. 8, 2000). Surgery andradiotherapy may be curative if the disease is found early, but currentdrug therapies for metastatic disease are mostly palliative and seldomoffer a long-term cure. Even with the new chemotherapies entering themarket, improvement in patient survival is measured in months ratherthan in years, and the need continues for new drugs effective both incombination with existing agents as first line therapy and as second andthird line therapies in treatment of resistant tumors.

[0003] In the past, the most successful drug treatment regimens havecombined two or more agents, each of which has a different mechanism ofaction and each of which has antitumor activity when used individually.Even though their mechanisms of action differ, most of the agentscurrently used for chemotherapy of cancer, including alkylating agents,platinum analogs, anthracyclines and the camptothecin family oftopoisomerase inhibitors, have in common the property of severelydamaging DNA, hence their designation as “DNA-damaging agents”.Radiotherapy works similarly. Most DNA-damaging agents as well as themicrotubule-targeting agents (e.g., paclitaxel) cause the arrest ofcells at the G₂/M transition phase of the cell cycle, a major cell cyclecheckpoint where cells make a commitment to repair DNA or to undergoapoptosis if DNA damage al., Molecular and Biochemical Parasitology1:167-176 (1998) (substituents at the 2- and 3-positions)).

[0004] As a single agent, β-lapachone has demonstrated significantantineoplastic activity against human cancer cell lines atconcentrations typically in the range of 1-10 μM (IC₅₀). Cytotoxicityhas been demonstrated in transformed cell lines derived from patientswith promyelocytic leukemia (Planchon et al., Cancer Res., 55 (1996)3706), prostate (Li, C. J., et al., Cancer Res., 55 (1995) 3712),malignant glioma (Weller, M. et al., Int. J. Cancer, 73 (1997) 707),hepatoma (Lai, C. C., et al., Histol Histopathol, 13 (1998) 8), colon(Huang, L., et al., Mol Med, 5, (1999) 711), breast (Wuertzberger, S.M., et al., Cancer Res., 58 (1998) 1876), ovarian (Li, C. J. et al.,Proc. Natl. Acad. Sci. USA, 96(23) (1999) 13369-74), pancreatic (Li, Y.,et al., Mol Med, 6 (2000) 1008; Li, Y. Z., Mol Med, 5 (1999) 232), andmultiple myeloma cell lines, including drug-resistant lines (Li, Y., MolMed, 6 (2000) 1008). No cytotoxic effects were observed on normal freshor proliferating human PBMC (Li, Y., Mol Med, 6 (2000) 1008).

[0005] β-lapachone has been shown to be a DNA repair inhibitor thatsensitizes cells to DNA-damaging agents including radiation (Boothman,D. A. et al., Cancer Res, 47 (1987) 5361; Boorstein, R. J., et al.,Biochem. Biophys. Commun., 117 (1983) 30). Although its exactintracellular target(s) and mechanism of cell killing remain unknown,β-lapachone has also shown potent in vitro inhibition of human DNATopoisomerases I (Li, C. J. et al., J. Biol. Chem., 268 (1993) 22463)and II (Frydman, B. et al., Cancer Res. 57 (1997) 620) with novelmechanisms of action. Unlike topoisomerase “poisons” (e.g.,camptothecin, etoposide, doxorubicin) which stabilize the covalenttopoisomerase-DNA complex and induce topoisomerase-mediated DNAcleavage, β-lapachone interacts directly with the enzyme to inhibitcatalysis and block the formation of cleavable complex (Li, C. J. etal., J. Biol. Chem., 268 (1993) 22463) or with the complex itself,causing religation of DNA breaks and dissociation of the enzyme from DNA(Krishnan, P. et al., Biochem Pharm, 60 (2000) 1367). β-lapachone andits derivatives have also been synthesized and tested as anti-viral andanti-parasitic agents (Goncalves, A. M., et al., Mol. Biochem.Parasitology, 1 (1980) 167-176; Schaffner-Sabba, K., et al., J. MedChem., 27 (1984) 990-994).

[0006] More specifically, β-lapachone appears to work by disrupting DNAreplication, causing cell-cycle delays in G1 and/or S phase, inducingeither apoptotic or necrotic cell death in a wide variety of humancarcinoma cell lines without DNA damage and independent of p53 status(Li, Y. Z. et al (1999); Huang, L. et al.). Topoisomerase I is an enzymethat unwinds the DNA that makes up the chromosomes. The chromosomes mustbe unwound in order for the cell to use the genetic information tosynthesize proteins; β-lapachone keeps the chromosomes wound tight, sothat the cell cannot make proteins. As a result, the cell stops growing.Because cancer cells are constantly replicating and circumvent manymechanisms that restrict replication in normal cells, they are morevulnerable to topoisomerase inhibition than are normal cells.

[0007] Another possible intracellular target for β-lapachone in tumorcells is the enzyme NAP(P)H:quinone oxidoreductase (NQO1). Biochemicalstudies suggest that reduction of β-lapachone by NQO1 leads to a “futilecycling” between the quinone and hydroquinone forms with a concomitantloss of reduced NADH or NAD(P)H (Pink, J. J. et al., J. Biol Chem., 275(2000) 5416). The exhaustion of these reduced enzyme cofactors may be acritical factor for the activation of the apoptotic pathway afterβ-lapachone treatment.

[0008] As a result of these findings, β-lapachone is actively beingdeveloped for the treatment of cancer and tumors. In WO00/61142, forexample, there is disclosed a method and composition for the treatmentof cancer, which comprises the administration of an effective amount ofa first compound, a G1 or S phase drug, such as a β-lapachone, incombination with a G2/M drug, such as a taxane derivative. Additionally,U.S. Pat. No. 6,245,807 discloses the use of β-lapachone, amongst otherβ-lapachone derivatives, for use in the treatment of human prostatedisease.

[0009] One obstacle, however, to the development of pharmaceuticalformulations comprising β-lapachone for parenteral and topicaladministration is the low solubility of β-lapachone in pharmaceuticallyacceptable solvents. β-lapachone is highly insoluble in water and hasonly limited solubility in common solvent systems used for topical andparenteral administration, specifically for intravenous and cutaneousdelivery of drugs. As a result, there is a need for improvedformulations of β-lapachone for parenteral and topical administration,which are both safe and readily bioavailable to the subject to which theformulation is administered.

SUMMARY OF THE INVENTION

[0010] The present invention is directed generally to pharmaceuticalcompositions containing β-lapachone for use in the treatment ofmammalian cancers and which overcome the disadvantages and obstacles ofprior art compositions. More specifically, the invention is directed topharmaceutical compositions containing β-lapachone, or a derivative oranalog thereof, and a pharmaceutically acceptable solubilizing carriermolecule for use in the treatment of mammalian cancers, including lung,breast, colon, ovarian and prostate cancers, multiple myeloma, malignantmelanoma, non-melanoma skin cancers, as well as proliferation disordersand dermatological conditions such as psoriasis. The pharmaceuticalcomposition may be complexed or combined with the pharmaceuticallyacceptable solubilizing carrier molecule to form a unitary compositionor an inclusion complex. The pharmaceutically acceptable solubilizingcarrier molecule is advantageously a water-solubilizing carrier moleculeor an oil-based solubilizing carrier molecule.

[0011] The present invention provides pharmaceutical compositions ofβ-lapachone, or a derivative or analog thereof, and a pharmaceuticallyacceptable solubilizing carrier molecule that enhances the solubility ofthe β-lapachone and renders it bioavailable in mammalian bodies andsuitable for parenteral and topical administration. The concentration ofβ-lapachone in solution is preferably at least 1 mg/ml, more preferablyat least 3 mg/ml, even more preferably at least 5 mg/ml. Forconcentrated pharmaceutical compositions, we contemplate concentrationsof β-lapachone of 10 mg/ml or greater.

[0012] The present invention also provides pharmaceutical compositionscontaining β-lapachone and pharmaceutically acceptable solubilizingcarrier molecules in combination with a taxane derivative or otheranticancer agent, for use in the treatment of mammalian cancers.

[0013] The present invention also provides formulations of β-lapachone,or a derivative or analog thereof, complexed with pharmaceuticallyacceptable solubilizing carrier molecules, wherein the complex can befreeze-dried and when subsequently reconstituted in aqueous solution issubstantially soluble.

[0014] The present invention further provides methods for treatingmammalian cancers by administering to a patient the pharmaceuticalcompositions and formulations of the present invention.

[0015] The present invention further provides methods for treatingcancer and for treating dermatologic conditions by administering to apatient afflicted with cancer or a dermatologic condition, an analog orderivative of β-lapachone, such as 4-aceotoxy-β-lapachone or4-acetoxy-3-bromo-β-lapachone.

[0016] The present invention also provides pharmaceutical kits whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of β-lapachone, or aderivative or analog thereof. Such kits may include, if desired, one ormore of various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc. Printed instructions, either asinserts or as labels, indicating quantities of the components to beadministered, guidelines for administration, and/or guidelines formixing the components, may also be included in the kit.

[0017] The above description sets forth rather broadly the moreimportant features of the present invention in order that the detaileddescription thereof that follows may be understood, and in order thatthe present contributions to the art may be better appreciated. Otherobjects and features of the present invention will become apparent fromthe following detailed description considered in conjunction with theaccompanying drawings. It is to be understood, however, that thedrawings are designed solely for the purposes of illustration and not asa definition of the limits of the invention, for which reference shouldbe made to the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The invention will be better understood by reference to theappended figures in which:

[0019]FIG. 1 is a bar graph illustrating the relative solubility ofβ-lapachone in aqueous solutions of various solubilizing agents;

[0020]FIG. 2 is a bar graph illustrating the solubility of β-lapachoneas a function of hydroxypropyl-β-cyclodextrin concentration (HPBCD);

[0021]FIG. 3 is an HPLC chromatogram of a 5 mg/ml β-lapachone solutionin 20% hydroxypropyl-β-cyclodextrin concentration;

[0022]FIG. 4 is a chart illustrating the inhibition of cancer cellsurvival by β-lapachone and Taxol®;

[0023]FIG. 5 is a chart showing the growth inhibitory profile ofβ-lapachone in combination with Taxol® against ovarian tumor cell linesas determined by MTT assay;

[0024]FIG. 6 is an isobologram showing synergistic drug-drug interactionfor β-lapachone and Taxol® in the OVCAR-3 ovarian tumor cell line;

[0025]FIG. 7 is an isobologram showing synergistic drug-drug interactionfor β-lapachone and Taxol® in the MDAH-2774 ovarian tumor cell line;

[0026]FIG. 8 is a graph illustrating the cytotoxic effect of β-lapachoneon Cisplatin-sensitive (A2780s) and Cisplatin-resistant (A2780DDP)ovarian cancer lines;

[0027]FIG. 9 is a bar graph illustrating the synergistic effect ofβ-lapachone plus Taxol® in mouse model of human ovarian carcinoma;

[0028]FIG. 10 is a bar graph illustrating that β-lapachone is equallyefficacious in the mouse model of human ovarian carcinoma whenformulated in HPBCD solution;

[0029]FIG. 11 illustrates anti-tumor activity of β-lapachone and Taxol®in human breast cancer xenograft model;

[0030]FIG. 12 illustrates preferred β-lapachone analogs and derivativesin accordance with the present invention;

[0031]FIG. 13 is a schematic illustrating the injection of RPMI 8226 MMcells and the resulting tumor formation in Bg-Nu-Xid mice;

[0032]FIG. 14 is a graph showing the average weight pattern of miceduring the study;

[0033]FIG. 15 is a graph showing the effect on β-lapachone/Hydroxypropylβ-cyclodextrin on tumor volume;

[0034]FIG. 16 is a graph showing the effect of β-lapachone/hydroxypropylβ-cyclodextrin on the survival of mice in both groups; and

[0035]FIG. 17 illustrates representative photomicrographs showing theeffect of β-lapachone/hydroxypropyl β-cyclodextrin on tumors, as well asliver, spleen, lung, heart, brain and kidneys.

DETAILED DESCRIPTION OF THE INVENTION

[0036] β-lapachone, as well as its derivatives and analogs thereof (alsoreferred to herein as the “active compounds”), are described in Li, C.J. et al., J. Biol. Chem., 1993. These active compounds can beincorporated into pharmaceutical compositions suitable for parenteraladministration. Such compositions typically comprise the active compoundand a pharmaceutically acceptable carrier, excipient, diluent oradjuvant. However, the low solubility of β-lapachone in mostpharmaceutically acceptable solvents has been an obstacle to thedevelopment of a suitable formulation for parenteral and topicaladministration, particularly intravenous and cutaneous administration,respectively. Table 1 illustrates the limited solubility of β-lapachonein common solvent systems used for intravenous delivery of drugs.Preclinical pharmacokinetic data produced to date suggest that the idealpeak plasma concentration is in the range of 10 μg/ml. To achieve thisplasma concentration, an intravenous formulation must have a β-lapachoneconcentration approaching 10 mg/ml and be able to be diluted 5×-10× withsterile fluids for intravenous administration, such as saline or D5W.TABLE 1 β-lapachone Solubility (mg/ml) Undiluted 5X dilution* SolventSystem (mg/ml) (mg/ml) Poloxamer 20% 2.0350 0.0331 Povidone K17 20%1.8250 0.0312 Povidone K12 20% 1.8600 0.0313 Tween 80 11.1700 1.6550EtOH 76% 10.6600 0.1025 PEG 400 11.6800 0.1400 Propylene Glycol 8.78000.0950 Trappsol 20% 1.4650 0.0300

[0037] The maximum solubility of β-lapachone in the solvents listed inTable 1 was about 12 mg/ml. Upon dilution, the solubility decreased morethan the dilution factor in all the systems. Although variouspreclinical studies have used a variety of common solvent systems, suchas lipiodol, peanut oil, Cremophor/ethanol or PEG4000, for i.p. and i.v.dosing, none of these approaches have yet demonstrated suitability fordevelopment of an i.v. formulation for use in the clinic. Combining,mixing and/or complexing β-lapachone, its derivatives or analogs, with apharmaceutically-acceptable water-solubilizing carrier molecule, whichis advantageously hydroxypropyl-β-cyclodextrin (HPBCD) increases theaqueous solubility of β-lapachone with concentrations as high as 20mg/ml in 50% HPBCD solution as illustrated in Table 2. TABLE 2β-lapachone HPBCD in (highest conc.) Water (mg/ml) 10% 3.07 20% 7.04 30%10.78 40% 15.77 50% 19.74

[0038] These β-lapachone/HPBCD solutions are stable for extended periodsat room temperature and can be further diluted with sterile fluids forIV administration (e.g., sterile saline, D5W) and held for at least 24hours without precipitation of β-lapachone. The β-lapachone/HPBCDsolutions may also be sterile filtered, lyophilized and readilyreconstituted in water. Experimentation has determined thatHPBCD@20%/β-lapachone@5 mg/ml provides an excellent concentration foreasy lyophilization and relatively fast reconstitution. The invention isnot limited in this respect, however, and concentrations of β-lapachoneas low as 1 mg/ml have been prepared and determined to be stable andcapable of being lyophilized and reconstituted. The combining orcomplexation of β-lapachone with HPBCD also appears to improve thestability of β-lapachone to photoreduction compared with complexation ofβ-lapachone with ethanol solutions.

[0039] Further study of β-lapachone in aqueous HPBCD solutions hasdemonstrated that the solubility of β-lapachone increases linearly withthe increase in HPBCD concentration. Upon 10 to 100 times dilution, thedecrease of β-lapachone concentration in all HPCD systems isproportional to the dilutions made.

[0040] Cyclodextrins are crystalline, nonhygroscopic cyclic oligomers ofα-D-glucopyranose derived from starch. As a result of a lack of rotationabout the bonds connecting the glucopyranose units, the cyclodextrinsare not cylindrical, but toroidal in shape. Because of this restrictedrotation they have a rigid structure with a central cavity whose sizevaries according to the number of glucopyranose units in the molecule.The three most common cyclodextins are α-cyclodextrin, β-cyclodextrinand γ-cyclodextrin, and which consist of six, seven and eightglucopyranose units respectively. Due to the arrangement of hydroxylgroups within the cyclodextrin molecule and the shape of the molecule,the internal surface of the cavity is hydrophobic, while the outsidesurface is hydrophilic. The primary hydroxyl groups are located on thenarrower (inner) side of the toroidal molecule, while the secondaryhydroxyl groups are located on the wider (outer) edge. This arrangementpermits the cyclodextrins to accommodate a wide variety of smallhydrophobic molecules within the hydrophobic cavity by forming aninclusion complex.

[0041] The HPBCD has seven glucopyranose units and has hydroxypropylgroups attached to each glucopyranose unit on the outer surface of thetoroidal structure. The solubility of HPBCD in water has been shown tobe far superior than that of β-cyclodextrin. The introduction of thehydroxypropyl groups into the β-cyclodextrin renders it more soluble bydisrupting the intramolecular hydrogen bonding between hydroxyl moietieson the cyclodextrin cavity. As a result, inclusion complexes formed byHPBCD will also have higher solubility in water compared to inclusioncomplexes formed by β-cyclodextrins. The degree of substitutiondetermines the solubility and complexation patterns. The lesser thesubstitution, the more the binding will be similar to that ofunsubstituted cyclodextrin in terms of binding, as well as solubility.Higher substitution renders the cyclodextrin more soluble in water butless binding. The degree of substitution of cyclodextrins is easilycontrolled.

[0042] When complexing β-lapachone, its derivatives or analogs, with awater-solubilizing carrier molecule in accordance with the presentinvention, the complexed solution generally becomes a unitarycomposition, or in the case where the water-solubilizing carriermolecule is a HPBCD, an inclusion complex is formed wherein theinsoluble β-lapachone, its derivatives or analogs, is within thecyclodextrin cavity. The invention is not limited, however, to theformation of a complex.

[0043] Although HPBCD is the preferred solubilizing agent, the inventionis not limited in this respect, and other water-solubilizing agents forcombining with β-lapachone, its derivatives or analogs, such asPoloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol 400, propylene glycol andTrappsol, are contemplated. Furthermore, the invention is not limited towater-solubilizing agents, and oil-based solubilizing agents such aslipiodol and peanut oil, may also be used.

[0044] Surfactants are also contemplated as part of the presentinvention for solubilization of β-lapachone, its derivatives or analogs.It is necessary, however that the surfactant(s) used must be present ata high enough level when β-lapachone, its derivatives or analogs, isdiluted in water so that there is sufficient surfactant to retain theβ-lapachone, derivative or analog in solution. However, there cannot betoo much surfactant to cause intolerable side effects.

[0045] Emulsions of β-lapachone, its derivatives or analogs, may also beformed and are contemplated by the present invention. Emulsions may beprepared which comprise a therapeutically effective amount ofβ-lapachone, its derivatives or analogs, in one or more emulsifiers oremulsifying agents which may result in an oil-in-water-type emulsion forparenteral administration. Suitable emulsifiers or emulsifying agentsmay include, but are not limited to, any pharmaceutically acceptableemulsifier, preferably phospholipids extracted from egg yolk or soybean, synthetic phosphatidyl cholines or purified phosphatidyl cholinesfrom vegetable origin. Hydrogenated derivatives can also be used, suchas phosphatidyl choline hydrogenated (egg) and phosphatidyl cholinehydrogenated (soya). Emulsifiers may also be non-ionic surfactants suchas poloxamers (for example Poloxamer 188 and 407), poloxamines,polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters orsorbitan fatty acid esters. Ionic surfactants may also be used such ascholic acid and deoxycholic acid or surface active derivatives or saltsthereof. The emulsifier can also be a mixture of one or more of theabove ingredients. The emulsion may additionally contain otheringredients such as buffers, stabilizers and other lipids.

[0046] Intralipid® is a fat emulsion for injection. Fat emulsions maycontain egg yolks, soybean oil, and safflower oil. Intralipid®, marketedin the U.S. as Liposyn II® and Liposyn III® (Abbot Laboratories, AbbottPark, Ill.), may be used as a source of calories and fatty acids tomaintain or increase the weight of the patient to whom it isadministered, or it may be used as a vehicle for poorly water-solublelipophilic drugs that cannot be injected directly. Intralipid® andLiposyn II® are marketed in both a 10% and 20% concentration. Inaccordance with the present invention, an emulsion comprisingβ-lapachone, its derivatives or analogs, and Intralipid®, or any otherpharmaceutically acceptable fat emulsion, may be prepared for parenteraladministration to a patient.

[0047] Recent in vitro and in vivo studies have shown that β-lapachonedemonstrates significant synergy with other chemotherapeutic andanticancer agents, particularly cis-platinum, and taxane derivatives,such as Taxol® (paclitaxel) (Bristol-Myers Squibb Co., New York, N.Y.).WO00/61142, for example, discloses a method and composition for thetreatment of cancer, which comprises the administration of an effectiveamount of a first compound, a G1 or S phase drug, such as a β-lapachone,in combination with a G2/M drug, such as a taxane derivative. By virtueof both its major functional characteristics—synergy with otherchemotherapy drugs and activity against resistant cells—the use ofβ-lapachone, its derivatives or analogs, may significantly increase therate of long term remission of numerous cancers, including ovarian,breast, prostate, colon, pancreatic, multiple myeloma, malignantmelanoma and non-melanoma skin cancers. β-lapachone, its derivatives oranalogs may also be used to treat proliferation disorders anddermatologic conditions, such as psoriasis.

[0048] As recited, the pharmaceutical composition and formulations ofthe present invention are intended for parenteral administration,preferably intravenous administration. The invention is not, however,limited in this respect and liquid pharmaceutical compositions andformulations in accordance with the present invention may be preparedfor oral ingestion.

[0049] Advantageously, pharmaceutical compositions for parenteraladministration comprise a desired amount of β-lapachone, its derivativesor analogs, complexed with HPBCD. Regular β-cyclodextrins are notsuitable for formulations intended for parenteral administration, butmay be used for the preparation of formulations for oral administration.As recited, experimentation has determined that the solubility ofβ-lapachone, its derivatives or analogs, increases linearly with theincrease in HPBCD concentration.

[0050] While β-lapachone is the preferred compound for use in thecomposition in accordance with the present invention, the invention isnot limited in this respect, and β-lapachone derivatives or analogs,such as lapachol, and pharmaceutical compositions and formulationsthereof are part of the present invention. Such β-lapachone analogsinclude those recited in PCT International Application PCT/US93/07878(WO 94/04145), which is incorporated by reference herein in itsentirety, and which discloses compounds of the formula:

[0051] where R and R₁ are each independently hydrogen, substituted andunsubstituted aryl, substituted and unsubstituted alkenyl, substitutedand unsubstituted alkyl and substituted or unsubstituted alkoxy. Thealkyl groups preferably have from 1 to about 15 carbon atoms, morepreferably from 1 to about 10 carbon atoms, still more preferably from 1to about 6 carbon atoms. The term alkyl unless otherwise modified refersto both cyclic and noncyclic groups, although of course cyclic groupswill comprise at least three carbon ring members. Straight or branchedchain noncyclic alkyl groups are generally more preferred than cyclicgroups. Straight chain alkyl groups are generally more preferred thanbranched. The alkenyl groups preferably have from 2 to about 15 carbonatoms, more preferably from 2 to about 10 carbon atoms, still morepreferably from 2 to 6 carbon atoms. Especially preferred alkenyl groupshave 3 carbon atoms (i.e., 1 propenyl or 2-propenyl), with the allylmoiety being particularly preferred. Phenyl and napthyl are generallypreferred aryl groups. Alkoxy groups include those alkoxy groups havingone or more oxygen linkage and preferably have from 1 to 15 carbonatoms, more preferably from 1 to about 6 carbon atoms. The substituted Rand R₁ groups may be substituted at one or more available positions byone or more suitable groups such as, for example, alkyl groups such asalkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbonatoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbonatoms or 2 to 6 carbon atoms, aryl groups having from six to ten carbonatoms, halogen such as fluoro, chloro and bromo, and N, O and S,including heteroalkyl, e.g., heteroalkyl having one or more hetero atomlinkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from1 to 10 carbon atoms or from 1 to 6 carbon atoms.

[0052] Other β-lapachone analogs contemplated in accordance with thepresent invention include those described in U.S. Pat. No. 6,245,807,which is incorporated by reference herein in its entirety, and whichdiscloses β-lapachone analogs and derivatives having the stricture:

[0053] where R and R₁ are each independently selected from hydrogen,hydroxy, sulfhydryl, halogen, substituted alkyl, unsubstituted alkyl,substituted alkenyl, unsubstituted alkenyl, substituted aryl,unsubstituted aryl, substituted alkoxy, unsubstituted alkoxy, and saltsthereof, where the dotted double bond between the ring carbonsrepresents an optional ring double bond.

[0054] Additional β-lapachone analogs and derivatives are recited in PCTInternational Application PCT/US00/10169 (WO00/61142), which isincorporated by reference herein in its entirety, and which disclosecompounds of the structure:

[0055] where R₅ and R₆ may be independently selected from hydroxy, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl,—(CH₂)_(n)-phenyl; and R₇ is hydrogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, —(CH₂)_(n)-amino,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, —(CH₂)_(n)-heterocycle, or—(CH₂)_(n)-phenyl, wherein n is an integer from 0 to 10.

[0056] Other β-lapachone analogs and derivatives are disclosed in U.S.Pat. No. 5,763,625, U.S. Pat. No. 5,824,700 and U.S. Pat. No. 5,969,163,as well is in scientific journal articles, such as Sabba et al, J MedChem 27:990-994 (1984), which discloses β-lapachone with substitutionsat one or more of the following positions: 2-, 8- and/or 9-positions.See also Portela et al., Biochem Pharm 51:275-283 (1996) (substituentsat the 2- and 9-positions); Maruyama et al, Chem Lett 847-850 (1977);Sun et al, Tetrahedron Lett 39:8221-8224 (1998); Goncalves et al,Molecular and Biochemical Parasitology 1:167-176 (1998) (substituents atthe 2- and 3-positions); Gupta et al., Indian Journal of Chemistry 16B:35-37 (1978); Gupta et al., Curr Sci 46:337 (1977) (substituents at the3- and 4-positions); DiChenna et al., J Med Chem 44: 2486-2489 (2001)(monoarylamino derivatives). Each of the above-mentioned references areincorporated by reference herein in their entirety.

[0057] More preferably, analogs and derivatives contemplated by thepresent application are intended to encompass compounds having thegeneral formula I and II:

[0058] where the dotted double bond between the ring carbons representsan optional ring double bond and where R and R₁ are each independentlyselected from hydrogen, hydroxy, sulfhydryl, halogen, substituted alkyl,unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl,substituted aryl, unsubstituted aryl, substituted alkoxy, unsubstitutedalkoxy, and salts thereof. The alkyl groups preferably have from 1 toabout 15 carbon atoms, more preferably from 1 to about 10 carbon atoms,still more preferably from 1 to about 6 carbon atoms. The term alkylrefers to both cyclic and noncyclic groups. Straight or branched chainnoncyclic alkyl groups are generally more preferred than cyclic groups.Straight chain alkyl groups are generally more preferred than branched.The alkenyl groups preferably have from 2 to about 15 carbon atoms, morepreferably from 2 to about 10 carbon atoms, still more preferably from 2to 6 carbon atoms. Especially preferred alkenyl groups have 3 carbonatoms (i.e., 1-propenyl or 2-propenyl), with the allyl moiety beingparticularly preferred. Phenyl and napthyl are generally preferred arylgroups. Alkoxy groups include those alkoxy groups having one or moreoxygen linkage and preferably have from 1 to 15 carbon atoms, morepreferably from 1 to about 6 carbon atoms. The substituted R and R₁groups may be substituted at one or more available positions by one ormore suitable groups such as, for example, alkyl groups having from 1 to10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups having from2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from sixto ten carbon atoms, halogen such as fluoro, chloro and bromo, and N, Oand S, including heteroalkyl, e.g., heteroalkyl having one or morehetero atom linkages (and thus including alkoxy, aminoalkyl andthioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms;and where R₅ and R₆ may be independently selected from hydroxy, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, —(CH₂)_(n)-heterocycle, or—(CH₂)_(n)-phenyl; and R₇ is hydrogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, —(CH₂)_(n)-amino,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, —(CH₂)_(n)-heterocycle, or—(CH₂)_(n)-phenyl, wherein n is an integer from 0 to 10.

[0059] Preferred analogs and derivatives also contemplated by theinvention include compounds of the following general formula III:

[0060] where R₁ is (CH₂)_(n)—R₂, where n is an integer from 0-10 and R₂is hydrogen, an alkyl, an aryl, a heteroaromatic, a heterocyclic, analiphatic, an alkoxy, an allyloxy, a hydroxyl, an amine, a thiol, anamide, or a halogen.

[0061] Analogs and derivatives also contemplated by the inventioninclude 4-acetoxy-β-lapachone, 4-acetoxy-3-bromo-β-lapachone,4-keto-β-lapachone, 7-hydroxy-β-lapachone, 7-methoxy-β-lapachone,8-hydroxy-β-lapachone, 8-methoxy-β-lapachone, 8-chloro-β-lapachone,9-chloro-β-lapachone, 8-methyl-β-lapachone and8,9-dimethoxy-β-lapachone.

[0062] Preferred analogs and derivatives also contemplated by theinvention include compounds of the following general formula IV:

[0063] where R₁-R₄ are each, independently, selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,—(CH₂)_(n)-heterocycle, or —(CH₂)_(n)-phenyl; or R₁ and R₂ combined area single substituent selected from the above group, and R₃ and R₄combined are a single substituent selected from the above groups, inwhich case — is a double bond.

[0064] Preferred analogs and derivatives also contemplated by thisinvention include dunnione and2-ethyl-6-hydroxynaphtho[2,3-b]-furan-4,5-dione.

[0065] Preferred analogs and derivatives also contemplated by theinvention include compounds of the following general formula V:

[0066] where R₁ is selected from H, CH₃, OCH₃ and NO₂.

[0067] Preferred compounds of the above generic formulas are illustratedin FIG. 12.

[0068] The solubilities of β-lapachone and its analogs in 40% (w/v)HPBCD solution as compared to water are shown in Tables 3 and 4. Todetermine solubilities, test compounds were first dissolved in ethanolto prepare standard solutions with concentrations in the range 2.5-10mg/ml, then were diluted with to 10 μg/ml with water. UV scans wereobtained of the 10 μg/ml standard solutions, and the wavelength ofmaximum absorbance and the absorbance at the maximum absorbancewavelength were determined. For each test compound 50 μl aliquots ofwater and of 40% HPBCD were added to individual Eppendorf tubescontaining approximately 1 mg of compound each. The tubes were heated ina 30° C. waterbath, vortexed, then centrifuged at 15,000 rpm for 5 min.This step was repeated, then the tubes were cooled to room temperaturefor 1 hour, then were centrifuged again. The supernatant from each tubewas diluted with water into the appropriate absorbance range, and the UVabsorbance was measured at the compound's absorbance maximum wavelength.The concentrations of these saturated solutions were then calculated byratio to the 10 μg/ml ethanolic standard solutions. As shown in Tables 3and 4 aqueous solubilities of the test compounds were increased by 7 to323 fold in the presence of 40% HPBCD. TABLE 3 Absorbance values ofβ-lapachone and its analogs in aqueous and in 40% (w/v)hydroxypropyl-β-cyclodextrin (HPBCD) solution Wavelength Absorbance ofat Maximum 10 μg/ml Aqueous Solution HPBCD Solution Absorbance, standardDil Dil Compound (nm) solution Factor Absorbance Factor Absorbanceβ-Lapachone 258 1.041 10 0.452 2000 0.73  (βL) 3-Bromo-βL 256 0.788 100.286 1000 0.545 3,4-dehydro-βL 262 0.71  10 0.171 1000 0.41  Dunnione262 0.944 100  0.449 5000 0.322 4-Acetoxy-βL 254 0.89  50 0.506  5000.373 4-Hydroxy-βL 254 0.973 50 0.742  500 0.596 4-keto-βL 280 1.216 501.224  500 1.07  3-Hydroxy-βL 256 0.995 200  0.687 2000 0.7273-(3-methyl-2- 258 0.697 20 0.233 1000 0.284 butenyl)-βL

[0069] TABLE 4 Solubilities of β-lapachone and its analogs in aqueousand in 40% (w/v) hydroxypropyl-β-cyclodextrin (HPBCD) solutionSolubility Solubility Solubility in Water in HPBCD Enhancement Compound(μg/ml) Solution (mg/ml) (−Fold) β-Lapachone (βL) 43 14.0 323 3-Bromo-βL36 6.9 191 3,4-dehydro-βL 24 5.8 240 Dunnione 476 17.0 36 4-Acetoxy-βL284 2.1 7.4 4-Hydroxy-βL 381 3.1 8.0 4-keto-βL 503 4.4 8.7 3-Hydroxy-βL1381 14.6 10.6 3-(3-methyl-2- 67 4.1 61 butenyl)-βL

[0070] Other particular formulations in accordance with the presentinvention are set forth herein below and in the Examples section. Ingeneral, the β-lapachone, its derivative and analog, compounds may beprepared in a number of ways well known to one skilled in the art oforganic synthesis. β-lapachone and its derivatives and analogs may besynthesized using methods generally described below, together withsynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as appreciated by those skilled in the art. Preferredmethods include, but are not limited to, those synthesis and formulationmethods described herein.

[0071] Numerous methods are known in the art for synthesizingβ-lapachone and/or derivatives or analogs thereof A first method isdescribed in Schaffner-Sabba, K., et al., β-Lapachone: Synthesis ofDerivatives and Activities in Tumor Models, J. Med. Chem, 27, (1984)990-994, and is known as the potassium salt method. A second method isdescribed in Sun, J. S. et al., A Preparative Synthesis of Lapachol andRelated Naphthoquinones, Tetrahedron Letters, 39 (1998) 8221-8224), andis know as the lithium salt method. These two methods both initiallyproduce lapachol, an intermediate from which β-lapachone is synthesized.Both of these methods require the formation of a metal salt.Additionally, Amaral, A., et al., in The Total Synthesis of β-lapachone,J. Heterocyclic Chem., 29 (1992) 1457-1460, describes the synthesis ofβ-lapachone α-naphthol in eight steps and results in an overall yield ofonly 23%. In U.S. Pat. No. 5,763,625, lapachol is first converted into3-bromolapachone, which is then converted in a two-step sequence into3-hydroxy-β-lapachone. Furthermore, as described in copending U.S.patent application Ser. No. 09/975,776, unlike the reported methods inwhich a metal (lithium or potassium) salt of 2-hydroxy-1,4-naphtoquinonewas prepared in situ by addition of lithium hydride or separately byaddition of potassium hydroxide to the quinone solution as the firststep and then reacting the metal salt with bromide compound to formlapachol, the process described in co-pending U.S. patent applicationSer. No. 09/975,776 eliminates this first step and commences directlywith 2-hydroxy-1,4-naphthoquinone to react with1-bromo-3-methyl-2-butene in the presence of sodium iodide and a weakbase such as triethylamine, pyridine, trimethylamine,N,N-diisopropylethylamine, 2,6-lutidine, to form lapachol from whichβ-lapachone is subsequently synthesized.

[0072] As discussed above, β-lapachone as a single agent has been shownto have significant cytotoxic activity for a wide variety of cancel celllines, with IC₅₀ values in the low (1-10) micromolar range. In vitrostudies have demonstrated that these micromolar concentrations ofβ-lapachone totally abolished colony formation when applied to tumorcell cultures in combination with IC₅₀ levels of Taxol®. These studieshave further shown that β-lapachone acts synergistically with Taxol®,which contains the active compound paclitaxel, to significantly augmenteffectiveness of either agent alone without attendant increases intoxicity (Li, C. J. et al., Proc Natl Acad Sci U.S.A. 96 (1999) 13369).

[0073] Potent inhibition of in vivo tumor growth by β-lapachone plusTaxol® has been demonstrated in a xenograft model of human ovariancancer in nude mice. Potent antitumor activity has also beendemonstrated in female nude mice bearing human breast cancer xenografts(discussed in detail in the Examples below).

[0074] Solubilized β-lapachone, its derivatives and analogs, may also becombined with other taxane derivatives and anticancer agents. In thecombination, solubilized β-lapachone, its derivatives and analogs, maybe admixed with the anticancer agent or taxane derivative, and providedin a single vial, or they may each be provided in a separate vial. Whenthe solubilized β-lapachone, its derivatives and analogs, and theanticancer agent or taxane derivative is provided in separate vials, thecontents of each vial may be administered to the patient simultaneouslyor sequentially.

[0075] In another embodiment, solubilized β-lapachone, its derivativesand analogs, may be administered in combination with radiation therapy.Advantageously, a patient will undergo radiation therapy a predeterminednumber of hours prior to or following β-lapachone, its derivatives andanalogs, administration as determined by the medical clinician treatingthe patient.

[0076] The type and amount of β-lapachone, its derivatives and analogs,and the HPBCD or other carrier used will vary widely depending on thespecies of the warm blooded animal or human, body weight, and tumorbeing treated. Likewise, the dosage administered will vary dependingupon known factors, such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;and the effect desired.

[0077] The dosage administered will vary depending upon known factorssuch as the pharmacodynamic characteristics of the particular activeingredient, and its mode and route of administration; age, sex, health,metabolic rate, absorptive efficiency and/or weight of the recipient;nature and extent of symptoms; kind of concurrent treatment, frequencyof treatment; and the effect desired. In a preferred embodiment, thedosage can be between approximately 0.1 mg/kg to 10 mg/kg administeredfrom between twice weekly to once every four weeks.

[0078] As used herein, the term “therapeutically effective amount” meansthat amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system animal or human thatis being sought by a researcher or clinician.

[0079] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. A dosage unit may comprise a single compound,i.e., β-lapachone, its derivatives and analogs, or mixtures thereof withother compounds or other cancer inhibiting compounds or tumor growthinhibiting compounds or anti-viral compounds. Compositions suitable forparenteral administration advantageously include aqueous sterileinjection solutions, but may also include non-aqueous solutions, whichmay contain anti-oxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. The formulations may bepresent in unit-dose or multi-dose containers, for example, sealed inampules and vials, and as discussed herein, may be stored in lyophilizedcondition requiring only the addition of the sterile liquid carrier, forexample, water, for injections, immediately prior to use. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsas known in the art for the preparation of such solutions. Thespecifications for the dosage unit forms of the invention are dictatedby and directly dependent on the unique characteristics of the activecompound and the particular therapeutic effect to be achieved, and thelimitations inherent in the art of compounding such an active compoundfor the treatment of individuals.

[0080] It should be understood that in addition to the ingredientsparticularly mentioned with regard to the specific compositions andformulations of the present invention, the compositions and formulationsof this invention may include other agents convention in the art havingregard to the type of formulation in question, for example, thosesuitable for oral administration may include flavoring and coloringagents.

[0081] In addition to the complex of β-lapachone, its derivatives andanalogs, with HPBCD in accordance with the present invention,pharmaceutical compositions suitable for parenteral administration viainjection or infusion may also include sterile aqueous solutions (wherewater soluble) or dispersions and sterile powders for the extemporaneouspreparation of sterile injectable solutions or dispersions. Forintravenous administration, suitable carriers include physiologicalsaline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS). The carrier can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyethylene glycol, andthe like), oil and suitable mixtures thereof. In all cases, thecomposition must be sterile and should be fluid to the extent that easysyringeability exists. It must be stable under the conditions ofmanufacture and storage and must be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol, sorbitol, sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent which delays absorption, forexample, aluminum monostearate and gelatin. Parenteral and intravenouscompositions may also include minerals and other materials to facilitatetheir compatibility with the type of injection or delivery system to beused. Additionally, solutions for parenteral administration may containa water soluble salt of the active compound, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

[0082] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in an appropriate solvent withone or a combination of ingredients enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the active compound into a sterile vehicle thatcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, methods of preparation arevacuum drying and freeze-drying that yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof. The β-lapachone, derivative or analogcomplexes described herein can be freeze-dried, then reconstituted inaqueous solution and be substantially soluble (see Example 5 below).

[0083] For oral administration in liquid dosage form, the oral drugcomponents are preferably combined with β-cyclodextrin and morepreferably hydroxylpropyl-β-cyclodextrin, however the invention is notlimited in this respect, and the oral drug components may be combinedwith any oral, non-toxic, pharmaceutically acceptable inert carrierssuch as ethanol, glycerol, water, oils and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like. Liquid dosage forms for oraladministration can also contain coloring and flavoring to increasepatient acceptance.

[0084] Additional examples of suitable liquid dosage forms may includesolutions or suspensions in water, pharmaceutically acceptable fats andoils, alcohols or other organic solvents, including esters, emulsions,syrups or elixirs, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules and effervescentpreparations reconstituted from effervescent granules. Such liquiddosage forms may also contain, additional solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents.

[0085] The active compounds may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0086] The active compounds of this invention are intended foradministration as treatment for cancer and the inhibition of tumors, byany means that produces contact of the active compounds with the agent'ssite of action in the body. As recited, the preferred mode ofadministering the β-lapachone, its derivatives and analogs, activeingredient is via parenteral administration, preferably intravenousadministration (bolus or infusion). The invention is not however limitedin this respect, and the active ingredients in accordance with thisinvention can be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination with other therapeutic agentswith the intention of inhibiting tumors. For example, the activecompounds may also be administered intraperitoneally, subcutaneously, orintramuscularly. The active compounds may also be formulated for topicaladministration for the treatment of skin cancers such as basal-cellcarcinoma, squamous-cell cancer, Kaposi's sarcoma and melanoma. Theactive compounds can be administered alone, but generally areadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice.

[0087] The present invention also includes methods for treating cancerby administering to a patient the compositions and formulations of thepresent invention. In a preferred embodiment, the method comprises theparenteral administration of the compositions and formulations to apatient, preferably via intravenous injection or infusion as describedabove. In another embodiment, the method comprises the topicaladministration of the compositions and formulation of the invention.“Topical application”, “applied topically”, “topical administration” and“administered topically”, are used interchangeably to mean the processof applying or spreading one or more compositions according to theinstant invention onto the surface of the skin of a subject in needthereof. Topical formulations may be comprised of an oil-in-water creamemulsion but is not limited in this respect. Topical formulationscontemplated by the present invention may include delayed releasecompositions capable of producing a slow release of the β-lapachoneanalogs and derivatives.

[0088] The formulations for topical administration may optionallycontain a wide variety of additional components intended to improve theoverall desirability, visual appearance, physical properties and/orphysical feel, but provided that such optional additives are physicallyand chemically compatible with the essential components described herein(supra), and do not unduly impair stability, safety or efficacy.Optional additives may be dispersed, dissolved or the like in thecarrier of the present compositions. Optional additives include possibleaesthetic agents, (e.g., absorbents including oil absorbents in the formof cosmetic clays and polymeric absorbents), abrasives, anti-cakingagents, antifoaming agents, additional anti-microbial agents, binders,buffering agents, bulking agents, cosmetic biocides, additionaldenaturants and penetrants (supra), cosmetic astringents, drugastringents, external analgesics, film formers, opacifying agents,fragrances, perfumes, pigments, colorings, skin soothing agents, pHadjusters, chelating agents, UV light absorbing agents, plasticizers,preservatives, preservative enhancers, depiliating agents, desquamationagents and exfoliants, collagens and breakdown products thereof,film-forming agents and the like. Representative examples of suchmaterials are disclosed in Harry's Cosmeticology, 7th Ed., Harry &Wilkinson (Hill Publishers, London 1982); in Pharmaceutical DosageForms—Disperse Systems; Lieberman, Rieger & Banker, Vols. 1 (1988) & 2(1989); Marcel Decker, Inc.; in The Chemistry and Manufacture ofCosmetics, 2nd. Ed., deNavarre (Van Nostrand 1962-1965); and in TheHandbook of Cosmetic Science and Technology, 1st Ed. Knowlton & Pearce(Elsevier 1993).

[0089] In other embodiments, compositions for use according to themethods of the invention also include compositions having a hydrophilicand hydrophobic phase. Non-limiting examples of suitable non-naturalhydrophobic phase components include: (i) a non-toxic andnon-carcinogenic mixtures of liquid hydrocarbons obtained from petroleum(64, 65); (ii) a non-toxic, non-carcinogenic colloidal system ofnonstraight-chain solid hydrocarbons and high-boiling liquidhydrocarbons in which most of the liquid hydrocarbons are micellar (64,66, 67); (iii) non-toxic and noncarcinogenic straight and branched chainhydrocarbons having from about 7 to about 40 carbon atoms, e.g.,dodecane, isododecane, squalane, cholesterol, hydrogenatedpolyisobutylene, docosane (i.e. a C.sub.22 hydrocarbon), hexadecane,isohexadecane (Permethyl.RTM 101A, Presperse, South Plainfield, N.J.),and the like; (iv) non-toxic and non-carcinogenic C.sub.1-30 alcoholesters of C.sub.1-30 carboxylic acids and of C.sub.2-30 dicarboxylicacids, including straight and branched chain materials as well asaromatic derivatives (e.g., diisopropyl sebacate, diisopropyl adipate,isopropyl myristate, isopropyl palmitate, methyl palmitate, myristylpropionate, 2-ethylhexyl palmitate, isodecyl neopentanoate,di-2-ethylhexyl maleate, cetyl palmitate, myristyl myristate, stearylstearate, isopropyl stearate, methyl stearate, cetyl stearate, behenylbehenrate, dioctyl maleate, dioctyl sebacate, diisopropyl adipate, cetyloctanoate, diisopropyl dilinoleate. (v) non-toxic and non-carcinogenicmono-, di- and triglycerides of C.sub.1-30 carboxylic acids, e.g.,caprilic/capric triglyceride, PEG-6 caprylic/capric triglyceride, PEG-8caprylic/capric triglyceride. (vi) non-toxic and non-carcinogenicalkylene glycol esters of C.sub.1-30 carboxylic acids, e.g., ethyleneglycol mono- and di-esters, and propylene glycol mono- and di-esters ofC.sub.1-30 carboxylic acids e.g., ethylene glycol distearate; (vii)non-toxic and non-carcinogenic propoxylated and ethoxylated derivativesof the foregoing materials; and (viii) non-toxic and non-carcinogenicC.sub.1-30 mono- and poly-esters of monosaccharides andoligosaccharides. Examples of liquid esters that may prove useful in thehydrophobic phase include glucose tetra-oleate; glucose tetra-esters ofsoybean oil fatty acids (unsaturated); mannose tetra-esters of mixedsoybean oil fatty acids; galactose tetra-esters of oleic acid; arabinosetetra-esters of linoleic acid; xylose tetra-linoleate; galactosepenta-oleate; sorbitol tetra-oleate; sorbitol hexa-esters of unsaturatedsoybean oil fatty acids; xylitol penta-oleate; sucrose tetra-oleate;sucrose pentaoletate; sucrose hexa-oleate; sucrose hepta-oleate; sucroseocta-oleate; and mixtures thereof.

[0090] In other embodiments, compositions suitable for topicaladministration according to the present invention include compositionshaving alternative carriers. Examples of alternative carriers includecross-linked polymeric compounds containing one or more monomers derivedfrom acrylic acid, substituted acrylic acids, and salts and esters ofthese acrylic acids and the substituted acrylic acids, wherein thecross-linking agent contains two or more carbon-carbon double bonds andis derived from either (i) an acrylic acid homopolymeric polyhydricalcohol, e.g., crosslinked homopolymers of acrylic acid monomer orderivative thereof (e.g., C₁₋₄ alkyl, —CN, or —COOH substituted), wherethe acrylic acid has substituents at the two and three carbon positions(e.g., acrylic acid, methacrylic acid, ethacrylic acid, and mixturesthereof); or (ii) a cross-linked acrylate copolymer having both anacrylic acid monomer (or derivative thereof) and a C₁₋₄ alcohol acrylateester monomer (or derivative thereof), and a second monomer which is along chain alcohol (e.g. C₈₋₄₀) acrylate ester monomer (or derivativethereof), e.g., acrylic acid, methacrylic acid, ethacrylic acid, andmixtures thereof. Combinations of the latter two types of polymers aremay also prove useful in certain compositions for use according to thetreatment methods of the invention.

[0091] In addition to treating disorders such as skin cancers, thepreparations of this invention may be used to treat a wide variety ofdermatologic conditions or disorders. Dermatologic conditions can be anydisorder associated with the skin. Dermatologic conditions include, butare not limited to, dermatitis conditions such as: Contact Dermatitis;Atopic Dermatitis; Seborrheic Dermatitis; Nummular Dermatitis; ChronicDermatitis of Hands and Feet; Generalized Exfoliative Dermatitis; StasisDermatitis; and Localized Scratch Dermatitis; bacterial infections ofthe skin, such as: Staphylococcal Diseases of the Skin, StaphylococcalScalded Skin Syndrome; Erysipelas; Folliculitis; Furuncles; Carbuncles;Hidradenitis Suppurativa; Paronychial Infections and Erythrasma;superficial fungal infections such as: Dermatophyte Infections; YeastInfections; Candidiasis; and Tinea Versicolor; parasitic infections ofthe skin such as: Scabies; Pediculosis; and Creeping Eruption; disordersof hair follicles and sebaceous; glands such as: Acne; Rosacea; PerioralDermatitis; Hypertrichosis; Alopecia; Pseudofolliculitis Barbae; andKeratinous Cyst; scaling papular diseases, such as: Psoriasis;Pityriasis Rosea; and Lichen Planus; pressure sores; benign tumors andmalignant tumors.

[0092] Additional information with regard to the methods of making thecompositions and formulations and the ingredients comprising thecompositions and formulations in accordance with the present inventioncan be found in standard references in the field, such as for example,“Remington's Pharmaceutical Sciences”, Mack Publishing Co., Easter, Pa.,15^(th) Ed. (1975).

[0093] The present invention also includes pharmaceutical kits whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of an active compound.Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. In a preferred embodiment, a kit is provided for thetreatment of a mammalian cancer comprising at least one vial containingβ-lapachone, or a derivative or analog thereof. In another preferredembodiment, a kit is provided for the treatment of a mammalian tumorcomprising one or more vials containing a complex of a therapeuticallyeffective amount of β-lapachone, or a derivative or analog thereof, anda pharmaceutically acceptable, water-solubilizing carrier molecule andfurther comprising, within in the same vial or a separate vial, ananticancer agent, particularly a taxane derivative.

[0094] Printed instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, may also beincluded in the kit. In the present disclosure it should be understoodthat the specified materials and conditions are important in practicingthe invention but that unspecified materials and conditions are notexcluded so long as they do not prevent the benefits of the inventionfrom being realized.

[0095] The invention is further defined by reference to the followingexamples, which are not meant to limit the scope of the presentinvention. It will be apparent to those skilled in the art that manymodifications, both to the materials and methods, may be practicedwithout departing from the purpose and interest of the invention.

EXAMPLES

[0096] 1. Evaluation of Acceptable Solvent Systems Known to SolubilizeHydrophobic Drug Substances

[0097] a. Preparation of β-Lapachone and Hydroxypropyl-β-Cyclodextrin(HPBCD) Solution

[0098] Various pharmaceutically acceptable solvent systems known tosolubilize hydrophobic drug substances were evaluated with β-lapachone.As shown in Table 5 below, solutions meeting the targeted minimumconcentration (10 mg/ml) were achieved in several of the solutionsevaluated. However, none of these systems could be diluted 5× withsterile saline without significant precipitation of the β-lapachone fromsolution. In addition, most of these co-solvents and surfactants havetheir own toxicity and tolerability issues that need to be managedduring high dose drug administration. TABLE 5 Undiluted 5X dilution*Solvent System (mg/ml) (mg/ml) Poloxamer (20%) 2.0350 0.0331 PovidoneK17 (20%) 1.8250 0.0312 Povidone K12 (20%) 1.8600 0.0313 Tween 8011.1700 1.6550 EtOH (76%) 10.6600 0.1025 PEG 400 11.6800 0.1400Propylene Glycol 8.7800 0.0950 Trappsol (20%) 1.4650 0.0300

[0099] In light of the above, two different strategies were used toenhance β-lapachone solubility in aqueous solution. First, β-lapachonewas treated with metal chelating agents, such as calcium and magnesium,to form soluble complexes; second, β-lapachone was treated with thesolubilizing agents β-cyclodextrin and γ-cyclodextrin to form solubleinclusion complexes. In order to evaluate these four reagents,¹⁴C-labeled β-lapachone in a small volume of ethanol was added toaqueous solutions of the reagents (or to PBS buffer as a control), thenthe relative solubility of β-lapachone in each of the solutions wasmeasured in terms of radioactivity remaining in the supernatant aftercentrifugation.

[0100] Specifically, to individual 1.5 ml Eppendorf tubes containing 900μl of PBS buffer were added the following: 8 mM CaCl₂ in PBS buffer, 8mM of MgCl₂ in PBS buffer, 8 mM β-cyclodextrin in PBS buffer, and 8 mMγ-cyclodextrin in PBS buffer. 10 μl of C¹⁴ labeled β-lapachone (40,000CPM, 0.55 μg) in 75% ethanol was then added to each tube. Aftervortexing and centrifuging at 13,000 rpm for 10 min, 100 μl of thesupernatant solution was counted for radioactivity using a BeckmanScintillation Counter. To the remaining mixture, 0.5 μg (50 μl of 10mg/ml solution) or 600 μg of β-lapachone in 75% ethanol was added. Aftervortexing and centrifuging at 13,000 rpm for 10 min, 100 μl of thesupernatant solution was counted again for radioactivity.

[0101] When 0.5 μg of β-lapachone was added, almost 100% of theβ-lapachone was present in the supernatant for all five aqueoussolutions. However, when 600 μg of β-lapachone was added, onlyβ-cyclodextrin solution retained more than 50% of the β-lapachone in thesupernatant. The percentage of labeled β-lapachone in the supernatantwas determined by counting in a scintillation counter. FIG. 1illustrates the relative solubility of β-lapachone in aqueous solutionsof various solubilizing agents. In FIG. 1, solution 1 consisted of PBSbuffer, solution 2 consisted of 8 mM CaCl₂ in PBS buffer, solution 3consisted of 8 mM MgCl₂ in PBS buffer, solution 4 consisted of 8 mMβ-cyclodextrin in PBS buffer, and solution 5 consisted of 8 mMγ-cyclodextrin in PBS buffer.

[0102] b. Effect of Hydroxypropyl-β-Cyclodextrin (HPBCD) Concentrationon β-Lapachone Solubility

[0103] Because β-cyclodextrin is suitable for oral, but not forparenteral or topical use, its analog HPBCD was selected for furtherstudy. To examine the effect of HPBCD concentration on β-lapachonesolubility, β-lapachone in small volumes of ethanol was added to eightaqueous solutions with varying concentrations of HPBCD (0-16 mM or 0-25%(w/w)), then relative solubility was determined by measuring thepercentage of radioactivity remaining in the supernatant aftercentrifigation. In order to eliminate the possible effect of ethanol anddetermine if solubility enhancement can be maintained afterlyophilization, the mixtures were lyophilized and then re-dissolved intothe same volume of water. The percentage of β-lapachone in thesupernatant of the re-dissolved mixture was measured to ensure completeresolubilization of the lyophilized material.

[0104] Specifically, to individual 1.5 ml Eppendorf tubes, sufficientamounts of water, 50 mM HPCD solution ¹⁴C-labeled β-lapachone solutionin 75% ethanol, 10 mg/ml β-lapachone solution in ethanol, and 0.9% NaClsolution were added to prepare 1 ml solutions with componentconcentrations listed in the Table 6. TABLE 6 Tube # 1 2 3 4 5 6 7 8 9HPCD, Mm 0 0 1 2 4 6 8 12 16 ¹⁴C-β-lapachone, 60K 60K 60K 60K 60K 60K60K 60K 60K CPM β-lapachone,, mM 0 1 1 1 1 1 1 1 1 NaCl, % (w/v) 0.9 0.90.9 0.9 0.9 0.9 0.9 0.9 0.9

[0105] After vortexing and centrifuging at 13,000 rpm for 10 min, 100 μlof supernatant from teach tube was counted for radioactivity using aBeckman Scintillation Counter. The rest of the mixtures (900 μl each)were lyophilized and then re-dissolved in 900 μl of water. Aftervortexing and centrifuging at 13,000 rpm for 10 min, 100 μg/ml ofsupernatant from each tube was counted again for radioactivity.

[0106]FIG. 2 shows that β-lapachone solubility increases with increasedHPBCD concentration, and that the β-lapachone can be fully resolubilizedfollowing lyophilization.

[0107] c. Preparation of β-Lapachone and Hydroxypropyl-β-Cyclodextrin(HPBCD) Solution by Heating

[0108] A β-lapachone/HPBCD solution was prepared without priorsolubilization of the β-lapachone in ethanol solution. β-lapachone wascombined with aqueous solutions of HPBCD in varying concentrations andthe mixtures were heated to 70° C., then allowed to cool to roomtemperature. The cooled solutions were filtered (0.22μ), and the amountof the solubilized β-lapachone was measured by HPLC analysis. Thesolubility of β-lapachone in various aqueous solutions of HPBCD isprovided in Table 7. TABLE 7 HPBCD β-lapachone Conc. % (m/M) (mg/ml) 50(325) 19.7 40 (260) 15.8 30 (195) 10.8 20 (130) 7.4 10 (65) 3.1

[0109] A maximum concentration of 19.7 mg/ml of β-lapachone was achievedin 50% HPBCD solution (highest concentration tested). The addition ofsaline or ethanol did not significantly enhance the solubility ofβ-lapachone in HPBCD.

[0110] d. HPLC Analysis and UV Measurement of β-lapachone Solution in75% Ethanol and Aqueous Solution of β-lapachone-HPBCD Complex

[0111] 5 μg/ml solutions of β-lapachone were prepared for HPLC and UVanalysis by diluting either 200 μg/ml ethanolic solutions or 5 mg/mlHPBCD solutions with water. UV measurements at 258 nm were performedusing routine procedures with 2% ethanol or 200 μg/ml HPBCD as referencesolutions. For HPLC analysis, 100 μl of the resulting 5 μg/mlβ-lapachone solutions was injected into a C¹⁸ reverse phase analyticalcolumn, and a linear gradient from 25% to 75% B buffer in 10 min at flowrate of 1 ml/min was applied. Peaks were detected by UV absorption at258 nm and quantitated by peak area ratio to external standards.

[0112] The λ_(max) for β-lapachone was observed at 258 nm from the UVspectrum. UV measurements of β-lapachone solution at 258 nm showed anextinction coefficient of 26620

[0113] M⁻¹ cm⁻¹ for both β-lapachone alone and the β-lapachone-HPBCDcomplex.

[0114]FIG. 3 shows a typical HPLC chromatogram of a 5 mg/ml β-lapachonesolution in 20% HPBCD, diluted to 5 μg/ml in water for HPLC analysis.β-lapachone elutes at approximately 5.4 min. Chromatograms showed nodifference in retention times and peak integration areas betweenβ-lapachone alone at 5 μg/ml in water and the comparable 5 μl/mlβ-lapachone-HPBCD complex. These results suggest that the β-lapachone isnot complexed with HPBCD at low concentrations (i.e., 5 μg/ml). Whenincreasing quantities of HPBCD were added to the 5 μg/mlβ-lapachone-HPBCD solution, HPLC analysis showed that a peak eluting atthe void volume of the column (retention time of about 1.2 min) andpresumed to be the β-lapachone-HPBCD complex, increased with size with acorresponding reduction of the β-lapachone peak. However, under theanalytical conditions developed for β-lapachone quantitation, whichrequires dilution to 5 μg/ml, the integration of the peak at ˜5.4 minprovides accurate quantitation of the total β-lapachone in the solution.

[0115] e. β-lapachone Stability

[0116] The stability of β-lapachone solutions either in 75% ethanol oran aqueous β-lapachone-HPBCD complex form was monitored by HPLCanalysis. When stored in the dark at room temperatures, theβ-lapachone-HPBCD solution showed significantly better stability thanthe ethanolic solution. The HPBCD solution had no detectable degradationproduct peaks after 5 days of storage; and a single degradation productpeak at about 0.1% at a retention time of 3.28 min after 21 days ofstorage. By comparison, ethanolic solutions stored in the dark showedsignificant loss of the β-lapachone peak after 5 days of storage.Significant stability enhancement was also observed for theβ-lapachone-HPBCD solution as compared to β-lapachone in 75% ethanolsolution when both were exposed to light with normal room brightness atroom temperature. However, the β-lapachone-HPBCD solution is stillappreciably degraded upon exposure to light, with degradation productscomprising 3.4% of total peak area by day 21 of exposure.

[0117] The mechanism of degradation of β-lapachone in alcohol solutionshas been shown to involve photoreduction to a relatively stable,semireduced quinone radical (Ci, Xiohong, et al., J. Am. Chem. Soc.1989: 111, 1337-1343). In the above studies, the primary degradationproduct in ethanolic solutions was identified as the reduced(hydroquinone) form of β-lapachone through retention time comparisonswith the product prepared by reduction of β-lapachone with sodiumborohydride. This species, which elutes at approximately 6.9 min has notbeen detected in HPBCD solutions of β-lapachone, which seem to show adifferent degradative pathway.

[0118] 2. Lyophilization of the β-Lapachone/HPBCD Complex Solution

[0119] β-lapachone/HPBCD complex solution samples were prepared inaccordance with the procedure set forth in Example 1a and 1c. Thesamples were transferred into a lyophilization container and pre-cooledto 40° C. for 2 h. Vacuum was applied to the container for 12-20 hoursdepending on the sample(s) (number, size, composition and otherproperties and characteristics of the samples) to provide a freeze-driedproduct. The lyophilized sample(s) were reconstituted

[0120] with 5.9 ml of deionized water with agitation to provideβ-lapachone at 10 mg/ml. The results of the samples tested are shown inTable 8. TABLE 8 β-lapachone/HPBCD system tested (All at 80 mg/vial)Vol- ume Formulation (ml) Time to Dry/Reconstitute HPBCD @40%/β-lapachone @ 8 Long (˜20 hr)/Long (>10 min)  10 mg/ml (density =1.125) HPBCD @ 26%/β-lapachone @ 12 Short (˜13 hr)/Short (˜10 min) 6.7mg/ml HPBCD @ 20%/β-lapachone @ 16 Short (˜13 hr)/Short (˜5 min)   5mg/ml HPBCD @ 10%/β-lapachone @ 32 Long (>20 hr) 2.5 mg/ml

[0121] Based upon these results, HPBCD@40%/β-lapachone@10 mg/mlaccomplished the solubility requirement for 10 to 100 times dilution. Ifthe solution is stable under the storage conditions, it is a suitableparenteral solution without lyophilization. If lyophilization ispreferred, HPBCD@20%/β-lapachone@5 mg/ml was demonstrated to be a goodchoice for speedy freeze-drying and relatively fast reconstitution.

[0122] 3. In Vitro Study of β-Lapachone Combined with Taxol®

[0123] Micromolar concentrations of β-lapachone have been shown tototally abolish colony formation when applied to tumor cell cultures incombination with IC₅₀ levels of Taxol®. In these studies, exponentiallygrowing cells were seeded at 1,000 cells per well in six-well plates andallowed to attach for 48 h. β-lapachone and/or Taxol®, solubilized inDMSO, were added to the wells. Control wells were treated withequivalent volumes of DMSO. After 4 h cells were rinsed and fresh mediumwas added. Cultures were observed daily for 10-20 days and then werefixed and stained. Colonies of greater than 30 cells were scored assurvivors. As shown in FIG. 4, synergistic inhibition of cancer cellsurvival was seen for a wide spectrum of human carcinoma cells ofdifferent histotypes, including ovarian, breast, prostate, melanoma,lung and pancreatic cell lines. β-lapachone or Taxol® alone were muchless effective in decreasing cancer cell colony formation. The decreasedcell survival was shown to be due to death by the MTT and tryptan blueexclusion assays. DNA laddering formation and annexin staining indicatedthat cell death was due to apoptosis.

[0124] Drug-drug interaction of β-lapachone and Taxol® was furtherevaluated in two ovarian tumor cell lines, OVCAR-3 and MDAH-2774 usingisobologram analysis. The individual IC₅₀ values for each drug weredetermined and then combinations of the two drugs at fixed ratios oftheir IC₅₀ concentrations were applied to the cells. Following a 4-daycontinuous exposure, cell viability was determined by MTT assay. Asillustrated in FIGS. 5, 6 and 7, a pattern of synergistic cell kill wasdemonstrated by the combination of these two drugs in these cell lines.

[0125] In FIG. 5, when interpreting the combination curves, statisticalcomparisons were made with each test combination and the endpoints (100%β-lapachone and 100% Taxol®). A statistically significant observationrequires that a difference exists between the combination (β-lapachoneand Taxol®) absorbance value and both endpoint values (β-lapachone orTaxol® alone). If the majority of the values (≧3 of 5) are statistically(p<0.05) below the line, then synergy is described. In FIG. 6, the drugcombination is shown to be significantly different (p<0.05) than eitherdrug alone at 3 of the 5 combinations evaluated. In FIG. 7, the drugcombination is shown to be significantly more cytotoxic (p<0.05) thaneither drug alone at 5 of the 5 combinations evaluated.

[0126] β-lapachone has also been shown to be active againstcis-platinum-resistant cell lines. The ovarian line A2780DDP is highlycis-platinum (cisplatin) resistant, with an IC₅₀ concentration forcisplatin typically >100 μM. As shown in FIG. 8, β-lapachone as a singleagent is equally cytotoxic to both the highly resistant line and to theparent line from which it is derived (A2780s). In testing β-lapachoneagainst the cisplatin-resistant-cell lines, cells were exposed toβ-lapachone solutions for 4 h. The cells were then rinsed and freshmedium was added. Cultures were observed daily for 10-20 days and thenwere fixed and stained. Colonies of greater than 30 cells were scored assurvivors.

[0127] 4. In Vivo Studies of β-Lapachone Combined with Taxol®

[0128] Human ovarian cancer cells (36M2, originally isolated frommalignant ascites) were inoculated by i.p. injection into athymic femalenude mice 24 h after irradiation. In this model, metastatic foci formapproximately 1 week after inoculation, and tumor nodules of theperitoneum and malignant ascites develop in 4-5 weeks. Ten days aftertumor inoculation (10×10⁶ cells), treatment regimens were initiated. Thecontrol group was treated with vehicle alone. In each typical treatmentcycle, the β-lapachone alone group was treated with 25-50 mg/kg i.p. ofβ-lapachone in Lipiodol solution and the Taxol® alone group was treated

[0129] at 1 mg/kg i.p. (Taxol® formulation diluted in Lipiodol), bothfollowed 24 h later by i.p. injection of vehicle. In the combinationgroup, nude mice were treated with β-lapachone at 25-50 mg/kg, followed24 h later by Taxol® at 1 mg/kg. All groups were treated for 10 cycles,with a 1-day break between each cycle. Mice were sacrificed two weekslater after the last treatment cycle (on day 50) to assess antitumoractivity. Host toxicity was evaluated by general appearance and bodyweight.

[0130]FIG. 9 shows the representative results for one of threeindependent therapeutic experiments, each with 6 mice per group. Thedecrease in tumor number versus control was quite pronounced withβ-lapachone alone (˜75%). Mice treated with Taxol® alone showed aslightly smaller effect (˜60%), and both groups showed considerablereduction in the size of the tumor nodules and the amount of ascites. Inanimals treated with β-lapachone plus Taxol®, no malignant ascites wereseen on the laparotomy, and the peritoneum was clean except for zero tothree tiny foci per mouse. These foci were counted as tumor nodulesalthough they appeared to be fibrotic scars. Mice treated with thecombination regimen appeared healthy and did not lose body weightthroughout the treatment period, and no gross abnormalities in theinternal organs were noted in the autopsy.

[0131] A similar study in the human ovarian xenograft model wasperformed comparing β-lapachone in HPBCD solution with β-lapachone inLipiodol solution. As with the previous study, treatment was initiatedten days after IP inoculation of 10×10⁶ 36M2 human ovarian cancer cellsinto athymic female nude mice, 8 per group (animals were not irradiatedprior to tumor inoculation). The control group was treated with vehiclealone. In each typical treatment cycle, β-lapachone alone groupsreceived 25 or 10 mg/kg i.p. of β-lapachone in HPBCD solution and theTaxol® alone groups was treated at 1 mg/kg i.p. (Taxol formulationdiluted in Lipiodol), both followed 24 h later by i.p. injection ofvehicle. In two combination groups, mice were treated with β-lapachonein HPBCD at either 25 or 10 mg/kg, followed 24 h later by Taxol® at 1mg/kg. A third combination group received β-lapachone in Lipiodol at 25mg/kg, followed 24 h later by Taxol® at 1 mg/kg. All groups were treatedfor 6 cycles, with a 1-day break between each cycle. Mice weresacrificed on about Day 50 (about 4 weeks after last treatment) forassessment of antitumor activity.

[0132]FIG. 10 shows the results of this study. Mice treated withβ-lapachone in HPBCD solution showed the same reduction in tumor nodulesas mice treated with a comparable level of β-lapachone in Lipiodolsolution.

[0133] Potent anti-tumor activity was also demonstrated in female nudemice bearing human breast cancer xenografts (MCF-7 cell line). Treatmentof mice was initiated after subcutaneous tumor nodules reached ˜0.5 cmin diameter. As shown in FIG. 11, mice receiving six cycles ofβ-lapachone (50 mg/kg i.p. in Lipiodol solution) and Taxol® (1 mg/kgi.p., 24 h after β-lapachone dose) showed dramatic reduction of tumorvolume compared to controls. Furthermore, tumors in the treated mice didnot increase in size as of the follow-up. In FIG. 11, the volume ofsubcutaneous tumor xenograft is shown in chart A and the body weight ofthe mice measured for 6 weeks after cessation of treatment is shown inchart B.

[0134] 5. Study of β-Lapachone Formulation in Intralipid®

[0135] A 10 mg/ml concentrate of β-lapachone in ethanol was prepared.The concentrate was diluted 5×to provide 100-500 μl total. A 2 mg/mlconcentration of β-lapachone was prepared in 10% Intralipid® by dropwiseaddition of the ethanolic solution to the Intralipid® with vortexing. Noimmediate evidence of precipitation or emulsion breaking was observed.

[0136] This procedure was repeated wherein the concentrate was diluted10× to prepare 1 mg/ml β-lapachone in 10% Intralipid®. Ethanol solutionwas added dropwise to the Intralipid® with vortexing. No immediateevidence of precipitation or emulsion breaking was observed. After 3days, the 2 mg/ml preparation had crystals, and the 1 mg/ml preparationshowed no changes. After 6 days, the 1 mg/ml preparation still showed nochanges.

[0137] 6. Single Agent β-Lapachone Analog Inhibition

[0138] Several preferred β-lapachone analogs and derivatives inaccordance with the present invention as well as a dunnione analog and4-hexanoyloxy-1,2-naphthoquinone (as stated infra, see illustrations inFIG. 12) were evaluated for their growth inhibitory activity as comparedto β-lapachone (CO-501) in six human cancer cells lines: A2780 andA2780/CP (ovarian); MCF-7 (breast); HT-29 (colon); BxPC-3 (pancreas);and A549 (lung). The human tumor cell lines (purchased from ATCC,Rockville, Md.) were cultured at 37° C. (5% CO₂) in RPMI medium (RPMI;Nova Tech, Grand Island, N.Y.) containing 10% fetal bovine serum (FBS,Nova Tech). Aliquots of cells were seeded into each well of 96-wellmicrotiter plates at a final concentration of 10⁴ cells/well andincubated for 24 h prior to exposure to test compounds. Growthinhibitory activity of DMSO solutions of each compound were measured bythe MTS assay after 4 hours of treatment followed by 24-hour incubationwith drug-free medium. The MTS assay is a colorimetric assay based uponthe ability of viable cells to convert MTS, a novel tetrazolium compoundand electron-coupling reagent, to a colored formazan product that issoluble in cell culture medium. The cell concentration is thendetermined by measuring the absorbance of the formazan product at 490nm. Growth inhibition, expressed as IC₅₀, is calculated relative tovehicle-treated control cells. The results of 3 individual assays, eachof which involved 3 replicates for each dose level, are shown in Table9, below.

[0139] As expected, a dose-dependent inhibitory effect was observed forβ-lapachone (CO-501) in all six tumor cell lines. The dunnione analog(CO-506) showed an activity profile similar to CO-501, as was predictedfrom the literature. Of the three β-lapachone analogs and derivatives,CO-504 (4-acetoxy β-lapachone) also was very similar to CO-501 ininhibitory activity; CO-503 (4-hydroxy β-lapachone) was significantlyless active across all cell lines; and CO505 was inactive (no growthinhibition observed at concentrations as high as 20 μM). CO-507, anaphthoquinone derivative, was also inactive. TABLE 9 Growth inhibitoryactivity of β-lapachone (CO-501) and five analogs and derivatives Growthinhibitory activity (50% effective concentration, IC₅₀, expressed as μM)Cell Line CO-501 CO-503 CO-504 CO-505 CO-506 CO-507 Ovarian A2780(sensitive) Exp 1 2.11 2.35 1.83 * 2.47 * Exp 2 3.99 5.29 1.60 * 4.79 *Exp 3 0.876 4.857 1.19 * 3.23 * Mean ± SE 2.32 ± 0.91 4.16 ± 0.92 1.54 ±0.19 * 3.50 ± 0.68 * Ovarian A2780CP (resistant) Exp 1 4.47 7.42 0.678 *2.73 * Exp 2 1.61 9.38 4.00 * 3.85 * Exp 3 1.76 14.8 2.56 * 1.53 * Mean± SE 2.61 ± 0.93 10.5 ± 2.2  2.41 ± 0.96 * 2.70 ± 0.67 * Breast MCF-7Exp 1 2.37 18.8 2.59 * 2.64 * Exp 2 4.75 19.4 4.78 * 3.99 * Exp 3 2.1019.3 4.28 * 3.53 * Mean ± SE 3.07 ± 0.84 19.2 ± 0.17 3.88 ± 0.67 * 3.39± 0.40 * Colon HT-29 Exp 1 5.37 13.2 14.1 * 17.3 * Exp 2 11.4 11.06.67 * 13.4 * Exp 3 9.89 12.1 3.98 * 11.2 * Mean ± SE 8.89 ± 1.82 12.1 ±0.63 8.25 ± 3.03 * 14.0 ± 1.78 * Pancreas BxPC-3 Exp 1 11.6 * 10.5 *5.69 * Exp 2 5.68 * 13.5 * 8.40 * Exp 3 16.5 * 2.32 * 9.22 * Mean ± SE11.3 ± 3.12 * 8.74 ± 3.33 * 7.77 ± 1.07 * Lung A549 Exp 1 4.48 14.319.3 * 7.50 * Exp 2 4.73 7.63 6.87 * 12.7 * Exp 3 18.7 9.77 3.75 *15.3 * Mean ± SE 9.30 ± 4.69 10.6 ± 1.98 9.97 ± 4.74 * 11.8 ± 2.28 *

[0140] 7. In vivo Testing of β-Lapachone in Bg-Nu-Xid Mice

[0141] Chemicals. β-lapachone was synthesized and dissolved in 40%hydroxypropyl β-cyclodextrin at a concentration of 10 mg/mL and kept atroom temperature in a dark container. Hydroxypropyl β-cyclodextrin wasdissolved in distilled water at a concentration of 10 mg/mL and kept atroom temperature. MATRIGEL®, a basement membrane matrix was purchasedfrom Becton Dickinson Labware (BD Biosciences, Two Oak Park Drive,Bedford, Mass.) and was dissolved in Dulbecco's modified Eagle's mediumwith 50 μg/mL Gentamycin and kept frozen at −20° C. MATRIGEL® isextracted from the Engelbreth-Holm-Swarm mouse tumor, a tumor rich inextracellular matrix proteins. The major matrix components are laminin,collagen IV, entactin, and heparan sulfate proteoglycan (perlecan); thematrix also contains growth factors, matrix metalloproteinases (MMPs[collagenases]), and plasminogen activators, without any inhibitors ofmetalloproteinases (TIMPs). The MATRIGEL matrix is a solution at 4° C.and gels at room temperature to form a three-dimensional reconstitutedbasement membrane. This model system closely mimics the structure,composition, physical properties, and functional characteristics of thebasement membrane in vivo and provides a physiologically relevantenvironment for studies of cell morphology, biochemical function,migration or invasion, and gene expression. The frozen MATRIGEL® matrixwas thawed overnight at 4° C. before use.

[0142] Cell Cultures. RPMI8226 cells (a human multiple myeloma cellline) were provided Dr. William Dalton (Lee Moffit Cancer Center, Tampa,Fla.). They were maintained by frequent passages in RPMI 1640 (Cellgro®,Mediatech Inc., Herndon, Va.) containing 10% Fetal Bovine serum (FBS)(GibcoBRL, Life Technologies, Grand Island, N.Y.) supplemented with2×10⁻³M L-Glutamine, 100 units/mL penicillin (Pen), and 100 μg/mLstreptomycin (Cellgro®D, Mediatech Inc., Herndon, Va.) in 162 cm² cellculture flasks (Costar®, Corning Incorporated, Corning, N.Y.). Theexponentially growing cell lines were CD138+, CD38+/CD45RA-, EBVnegative, and pathogen free.

[0143] Mice. Forty male 6 week old Bg-Nu-Xid mice (deficient in T, B,and NK cells) were obtained from the FCRDC, Frederick, Bethesda, Md. andhoused at the Redstone animal facility at DFCI. These mice have 3separate mutations—Beige (Bg) autosomal recessive mutation associatedwith impaired chemotaxis and motility of macrophages & deficiency of NKcells; the nude (nu) autosomal recessive mutation associated withdepletion of T cells due to thymic agenesis; and the X-linked immunedefect (xid) which produces functional defects of B lymphocytes. Theanimals were raised in a barrier facility in cages with saw dust beddingand laminar air at 19-22° C. Rodent food and sterile drinking water weresupplied ad libitum. The mice were quarantined to rule out developmentof any disease. One mouse died during transport, and 5 others were lostbecause of dehydration (n=2), probable infection (n=2) and excessivebleeding due to trauma (n=1). After 1 week, enrofloxacin (a quinoloneantibiotic) was added in drinking water of all mice. All proceduresinvolving animals were approved by and performed according to guidelinesof the Institutional Animal Care and Use Committee of the Dana FarberCancer Institute (DFCI).

[0144] Histologic Analysis. The mice were sacrificed when the tumorreached 20 mm in their largest diameter or they became moribund, as perthe policy of the Animal Protocol Committee at Dana Farber CancerInstitute. The mice were anesthetized with isoflurane, and retroorbitalblood was collected. The mice were sacrificed by cervical dislocation.The tumors were dissected from the soft tissue (fascia, muscle, skin,etc.) and were fixed in 10% neutralized formalin. Liver, spleen,kidneys, lung, heart and brain from each group were also removed andfixed in formalin. The tissues were dehydrated and embedded in paraffinblocks. They were sectioned into slices 5 μm thick, stained withhematoxylin and eosin (HE), and examined by light microscopy forevidence of apoptosis.

[0145] Statistical Analysis. Statistical analysis was done using thestudent's ‘t’ test for comparing the differences in tumor volumes anddegree of apoptosis between lapachone and control groups. p value of<0.05 was considered significant.

[0146] Design Thirty four mice were included in the study. RPMI 8226(3×10⁷) multiple myeloma cells were washed 3 times, re-suspended in 100μL RPMI 1640, and injected subcutaneously in the right flank of all micealong with 100 μL of MATRIGEL® matrix using a hypodermic 27G needle and1 mL syringe. The mice were observed for well being and development oftumors daily, and were weighed weekly.

[0147] Localized palpable tumors developed in all mice (n=34) by a meanof 7 days after injection of RPMI 8226 cells. Once the tumors werepalpable, they were measured by hand held vernier calipers in 2orthogonal diameters every other day. Thirty-one mice were randomized toβ-lapachone (n=16) and control (n=15) groups. The mice in the controlgroup received 50 mg/kg body weight of 40% hydroxypropyl β-cyclodextrinsolution intraperitoneally at the lower left abdominal area every otherday. The mice in the β-lapachone group received β-lapachone in 40%hydroxypropyl β-cyclodextrin at 50 mg/kg body weight intraperitoneallyevery alternate day (FIG. 13). The usual volume at each injection was125 μL. The diameters of the tumors were recorded, and the volumes werecalculated using standard formula for cylindrical objects i.e.0.523×(Smaller diameter)²×Larger diameter. Mice were sacrificed when thetumor was >20 mm in largest diameter or they became moribund.

[0148] This xenograft mouse model is attractive because it is easilyestablished, allows monitoring growth of subcutaneous tumors by externalmeasurements, and can be used to study the effects of variouschemotherapeutic agents. Rapidly growing tumors may show some areas ofapoptosis/necrosis, but in our experience that has not been a majorobstacle in the evaluation of cytotoxicity of various novel potentialtherapeutic agents. Similar models have been reported previously usinganti-gp130 agonist monoclonal antibodies (B1+I2) to study growth andimmortalization of multiple myeloma patient cells (Reme et al. Br JHaematol 114:406, 2001) and using anti-human IL-6R antibody PM1 and antihuman IL-6 antibody MH166, to inhibit growth of IL-6 dependent cell line(S6B45) (Suzuki et al. Eur J Immunol 22:1989, 1992). Various animalmodels for testing multiple myeloma therapeutic agents have beenreported previously (Gado et al. Haematologica 86: 227, 2001; Dallas etal. Blood 93:1697, 1999; Manning et al. Immunol Cell Biol 73:326, 1995;Takura et al. Cancer Res 26:2564, 1996; Potter et al. J Exp Med 161:996,1985; Yaccoby et al. Blood 92:2908, 1998; Urashima et al. Blood 90:754,1997).

[0149] Determination of β-lapachone and cyclodextrin toxicity. Mice inboth groups tolerated β-lapachone and hydroxypropyl β-cyclodextrin well.No mice died in either group and all gained weight (FIG. 14). There wasno evidence of overt toxicity of β-lapachone or hydroxypropylβ-cyclodextrin in either cohort. One mouse developed iatrogenicintra-peritoneal hemorrhage after injection of β-lapachone whichresolved in 36 h. Mild tubular vacuolization of kidneys in bothβ-lapachone and control groups was also found. Since this effect waspresent in both groups, hydroxypropyl β-cyclodextrin is implicated, ashas been previously reported for cyclodextrins (Frank et al. Am J Pathol83:367, 1976) and these nephrotoxic changes are reversible withcessation of treatment (Donaubauer et al. Regul Toxicol Pharmacol27:189, 1998).

[0150] Effects on β-lapachone tumor volume. Mice in control groupreceived a maximum of 6 doses of hydroxypropyl β-cyclodextrin, whereasthe mice in the β-lapachone group were able to receive a maximum of 8doses of this agent. There was a statistically significant decrease intumor volume of mice in β-lapachone group (p=0.007) versus control group(FIG. 15) by day 11. Importantly, survival was greater at day 5, 7, 9,11, 13, 15 and 17 in the β-lapachone group compared to controls (FIG.16), suggestive of slower tumor growth in β-lapachone group.

[0151] Histologic Staining. Histopathologic examination revealed thattumors were not encapsulated and were locally invasive to soft tissues,including muscle, without any distant metastasis. Tumors werevascularized by blood vessels of murine origin, with a minor variabledegree (0-10%) of cell death primarily in their cores. Apoptosis wasassessed histopathologically on the basis of (1) chromatin condensationand aggregation near the nuclear membrane with convolution of thenuclear membrane; (2) enlarged and abnormally granular nucleolus; (3)shrinkage and rounding of cells; (4) blebbing of cell membranes; and (5)minor dilation of endoplasmic reticulum and mitochondria There was astatistically significant increase in MM cell apoptosis (p=0.001) intumors in the β-lapachone (mean±SD=41.1%±12.7) versus control(mean±SD=20.0%±10.4) groups, as assessed by two blinded independentobservers using light microscopy (FIG. 17A).

[0152] There was no microscopic evidence of any toxicity of β-lapachoneor hydroxypropyl β-cyclodextrin on liver, heart, lung, brain, and spleenin mice in either β-lapachone or control groups (FIG. 17B, C, D, E, F).Kidneys from mice in both groups showed mild tubular vacuolization,suggesting tubular toxicity of hydroxypropyl β-cyclodextrin (FIG. 17G,H). This toxicity is not expected to be seen at the anticipatedtreatment doses in humans based on with previous drugs formulated inHPBCD. These results indicate that β-lapachone, formulated in HPBCD, issafe and effective at inhibiting tumor cell growth, associated withprolonged host survival in vivo. Thus it can be concluded that beta laphas significant anti-tumor activity with minimal toxicity and can beused to treat multiple myeloma in vivo.

Equivalents

[0153] Although particular embodiments have been disclosed herein indetail, this has been done by way of example for purposes ofillustration only, and is not intended to be limiting with respect tothe scope of the appended claims, which follow. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made to the invention without departing fromthe spirit and scope of the invention as defined by the claims. Theclaims presented are representative of the inventions disclosed herein.Other, unclaimed inventions are also contemplated. It is to beunderstood that the drawings are not necessarily drawn to scale, butthat they are merely conceptual in nature. Applicants reserve the rightto pursue such inventions in later claims.

What is claimed is:
 1. A pharmaceutical composition comprising atherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and a pharmaceutically acceptable solubilizing carriermolecule.
 2. The pharmaceutical composition of claim 1, wherein thepharmaceutical composition comprises a complex or solution of thetherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and the pharmaceutically acceptable solubilizing carriermolecule.
 3. The pharmaceutical composition of claims 1 or 2, whereinthe composition is an aqueous solution or an oil solution.
 4. Thepharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable solubilizing carrier molecule is a water-solubilizing carriermolecule selected from the group consisting of Poloxamer, Povidone K17,Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol(PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogsthereof, beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin oranalogs thereof.
 5. The pharmaceutical composition of claim 4, whereinthe water-solubilizing carrier molecule is beta-cyclodextrin.
 6. Thepharmaceutical composition of claim 5, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 7. The pharmaceutical composition ofclaim 1, wherein the pharmaceutically acceptable solubilizing carriermolecule is an oil-based solubilizing carrier molecule.
 8. Thepharmaceutical composition of claim 7, wherein the oil-basedsolubilizing carrier molecule is lipiodol.
 9. The pharmaceuticalcomposition of claim 3, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 10. The pharmaceutical composition ofclaim 1, wherein the therapeutically effective amount of Beta-lapachone,or a derivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule exist as an emulsion.
 11. A pharmaceuticalcomposition comprising a therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable solubilizing carrier, which when dilutedwith an aqueous solution for parenteral administration, remainssubstantially soluble in the aqueous solution.
 12. The pharmaceuticalcomposition of claim 11, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, is complexed with thepharmaceutically acceptable water solubilizing carrier.
 13. Thepharmaceutical composition of claim 11, wherein the pharmaceuticallyacceptable solubilizing carrier molecule is a water-solubilizing carriermolecule selected from the group consisting of Poloxamer, Povidone K17,Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol(PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogsthereof, beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin oranalogs thereof.
 14. The pharmaceutical composition of claim 13, whereinthe water-solubilizing carrier molecule is beta-cyclodextrin.
 15. Thepharmaceutical composition of claim 14, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 16. The pharmaceutical composition ofclaim 11, wherein the pharmaceutically acceptable solubilizing carriermolecule is an oil-based solubilizing carrier molecule.
 17. Thepharmaceutical composition of claim 16, wherein the oil-basedsolubilizing carrier molecule is lipiodol.
 18. The pharmaceuticalcomposition of claim 11, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 19. The pharmaceutical composition ofclaim 12, wherein the complex comprises a dosage unit in the rangebetween 0.1 mg/kg to 10 mg/kg administered from between twice weekly toonce every four weeks.
 20. The pharmaceutical composition of claim 11,wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule exist as an emulsion.
 21. A formulation ofBeta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable solubilizing carrier molecule, wherein theformulation can be freeze-dried and when subsequently reconstituted inaqueous solution is substantially soluble.
 22. The formulation of claim21, wherein the Beta-lapachone, or a derivative or analog thereof iscomplexed with the pharmaceutically acceptable solubilizing carriermolecule.
 23. The formulation of claim 21, wherein the pharmaceuticallyacceptable solubilizing carrier molecule is a water-solubilizing carriermolecule selected from the group consisting of Poloxamer, Povidone K17,Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol(PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogsthereof, beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin oranalogs thereof.
 24. The formulation of claim 23, wherein thewater-solubilizing carrier molecule is beta-cyclodextrin.
 25. Theformulation of claim 24, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 26. The formulation of claim 21,wherein the concentration of Beta-lapachone in solution is at least 1mg/ml.
 27. The formulation of claim 21, wherein the Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule exist as an emulsion.
 28. A kit for thetreatment of a mammalian cancer comprising at least one vial containingBeta-lapachone, or a derivative or analog thereof, according to any oneof claims 1, 11 or
 21. 29. A pharmaceutical composition comprising atherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and a pharmaceutically acceptable solubilizing carriermolecule, and further comprising a second anticancer agent and apharmaceutically acceptable carrier.
 30. The pharmaceutical compositionof claim 29, wherein the composition comprises a complex or solution ofthe therapeutically effective amount of Beta-lapachone, or a derivativeor analog thereof, and the pharmaceutically acceptable solubilizingcarrier molecule, and further comprises the second anticancer agent anda pharmaceutically acceptable carrier.
 31. The pharmaceuticalcomposition of claims 29 or 30, wherein the second anticancer agent is ataxane derivative.
 32. The pharmaceutical composition of claim 31,wherein the taxane derivative is paclitaxel.
 33. The pharmaceuticalcomposition of claims 29 or 30, wherein the composition is an aqueoussolution or an oil solution.
 34. The pharmaceutical composition of claim29, wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule is admixed with the second anticanceragent and the pharmaceutically acceptable carrier and contained in asingle vial.
 35. The pharmaceutical composition of claim 29, wherein thetherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and the pharmaceutically acceptable solubilizing carriermolecule is contained in a first vial, and the second anticancer agentand the pharmaceutically acceptable carrier are contained in a secondvial.
 36. The pharmaceutical composition of claim 29, wherein thepharmaceutically acceptable solubilizing carrier molecule is awater-solubilizing carrier molecule selected from the group consistingof Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol,Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin oranalogs thereof, and gamma-cyclodextrin or analogs thereof.
 37. Thepharmaceutical composition of claim 36, wherein the water-solubilizingcarrier molecule is beta-cyclodextrin.
 38. The pharmaceuticalcomposition of claim 37, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 39. The pharmaceutical composition ofclaim 29, wherein the pharmaceutically acceptable solubilizing carriermolecule is an oil-based solubilizing carrier molecule.
 40. Thepharmaceutical composition of claim 39, wherein the oil-basedsolubilizing carrier molecule is lipiodol.
 41. The pharmaceuticalcomposition of claim 33, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 42. The pharmaceutical composition ofclaim 29 wherein the therapeutically effective amount of Beta-lapachone,or a derivative or analog thereof, and the pharmaceutically acceptablewater solubilizing carrier molecule, and the second anticancer agent andthe pharmaceutically acceptable carrier exist as an emulsion.
 43. A kitfor the treatment of a mammalian tumor comprising one or more vialscontaining a therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and a pharmaceutically acceptablesolubilizing carrier molecule and further comprising, within in the samevial or a separate vial, a second anticancer agent.
 44. The kit of claim43, wherein the one or more vials contain a complex of thetherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and the pharmaceutically acceptable solubilizing carriermolecule and further comprising, within in the same vial or a separatevial, the second anticancer agent.
 45. The kit of claims 43 or 44,wherein the second anticancer agent is a taxane derivative.
 46. The kitof claim 45, wherein the taxane derivative is paclitaxel.
 47. The kit ofclaims 43 or 44, wherein the pharmaceutically acceptable solubilizingcarrier molecule is a water-solubilizing carrier molecule selected fromthe group consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80,ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propyleneglycol, Trappsol, alpha-cyclodextrin or analogs thereof,beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin or analogsthereof.
 48. The kit of claim 47, wherein the water-solubilizing carriermolecule is beta-cyclodextrin.
 49. The kit of claim 48, wherein thebeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin.
 50. The kit ofclaims 43 or 44, wherein the solubilizing carrier molecule is anoil-based solubilizing carrier molecule.
 51. The kit of claim 50,wherein the oil-based solubilizing carrier molecule is lipiodol.
 52. Thekit of claims 43 or 44, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 53. A method for treating cancercomprising administering to a patient a pharmaceutical compositioncomprising a therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and a pharmaceutically acceptablesolubilizing carrier molecule.
 54. The method of claim 53, wherein thepharmaceutical composition comprises a complex or solution of thetherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and the pharmaceutically acceptable solubilizing carriermolecule.
 55. The method of claims 53 or 54, wherein the composition isan aqueous solution or an oil solution.
 56. The method of claim 53,where the pharmaceutically acceptable solubilizing carrier molecule is awater-solubilizing carrier molecule selected from the group consistingof Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol,Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin oranalogs thereof, and gamma-cyclodextrin or analogs thereof.
 57. Themethod of claim 56, wherein the water-solubilizing carrier molecule isbeta-cyclodextrin.
 58. The method of claim 57, wherein thebeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin.
 59. The method ofclaim 53, wherein the pharmaceutically acceptable solubilizing carriermolecule is an oil-based solubilizing carrier molecule.
 60. The methodof claim 59, wherein the oil-based solubilizing carrier molecule islipiodol.
 61. The method of claim 55, wherein the concentration ofBeta-lapachone in solution is at least 1 mg/ml.
 62. The method of claim53, wherein the pharmaceutical composition is administered parenterally.63. The method of claim 62, wherein the pharmaceutical compositioncomprises a dosage unit in the range between 0.1 mg/kg to 10 mg/kgadministered from between twice weekly to once every four weeks.
 64. Themethod of claims 53, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable solubilizing carrier molecule exist as anemulsion.
 65. A method for treating cancer comprising administering to apatient a pharmaceutical composition comprising a therapeuticallyeffective amount of Beta-lapachone, or a derivative or analog thereof,and a pharmaceutically acceptable solubilizing carrier molecule, whichwhen diluted with an aqueous solution for parenteral administration,remains substantially soluble in the aqueous solution.
 66. The method ofclaim 65, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, is complexed with thepharmaceutically acceptable solubilizing carrier.
 67. The method ofclaim 65, wherein the pharmaceutically acceptable solubilizing carriermolecule is a water-solubilizing carrier molecule selected from thegroup consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80,ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propyleneglycol, Trappsol, alpha-cyclodextrin or analogs thereof,beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin or analogsthereof.
 68. The method of claim 67, wherein the water-solubilizingcarrier molecule is beta-cyclodextrin.
 69. The method of claim 68,wherein the beta-cyclodextrin is hydroxypropyl-beta-cyclodextrin. 70.The method of claim 65, wherein the pharmaceutically acceptablesolubilizing carrier molecule is an oil-based solubilizing carriermolecule.
 71. The method of claim 70, wherein the oil-based solubilizingcarrier molecule is lipiodol.
 72. The method of claim 65, wherein theconcentration of Beta-lapachone in solution is at least 1 mg/ml.
 73. Themethod of claim 65, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable water solubilizing carrier molecule exist asan emulsion.
 74. A method for treating cancer comprising administeringto a patient a formulation of Beta-lapachone, or a derivative or analogthereof, and a pharmaceutically acceptable, solubilizing carriermolecule, wherein the complex can be freeze-dried and when subsequentlyreconstituted in aqueous solution is substantially soluble.
 75. Themethod of claim 74, wherein the Beta-lapachone, or a derivative oranalog thereof, is complexed with the pharmaceutically acceptable,solubilizing carrier.
 76. The method of claim 74, wherein thepharmaceutically acceptable solubilizing carrier molecule is awater-solubilizing carrier molecule selected from the group consistingof Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol,Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin oranalogs thereof, and gamma-cyclodextrin or analogs thereof.
 77. Themethod of claim 76, wherein the water-solubilizing carrier molecule isbeta-cyclodextrin.
 78. The method of claim 77, wherein thebeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin.
 79. The method ofclaim 74, wherein the concentration of Beta-lapachone in solution is atleast 1 mg/ml.
 80. The method of claim 74, wherein the formulation isadministered parenterally.
 81. The method of claim 80, wherein saidpharmaceutical composition comprises a dosage unit in the range between0.1 mg/kg to 10 mg/kg administered from between twice weekly to onceevery four weeks.
 82. The method of claim 74, wherein thetherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and the pharmaceutically acceptable solubilizing carriermolecule exist as an emulsion.
 83. A method for treating cancercomprising administering to a patient a pharmaceutical compositioncomprising a therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and a pharmaceutically acceptable,solubilizing carrier molecule, and further comprising a secondanticancer agent and a pharmaceutically acceptable carrier.
 84. Themethod of claim 83, wherein the pharmaceutical composition comprises acomplex of the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptable,solubilizing carrier molecule, and further comprising the secondanticancer agent and a pharmaceutically acceptable carrier.
 85. Themethod of claim 83 or 84, wherein the second anticancer agent is ataxane derivative.
 86. The method of claim 85, wherein the taxanederivative is paclitaxel.
 87. The method of claims 83 or 84, wherein thecomposition is an aqueous solution or an oil solution.
 88. The method ofclaim 83, wherein said therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable solubilizing carrier molecule is admixedwith the second taxane derivative and the pharmaceutically acceptablecarrier and contained in a single vial.
 89. The method of claim 83,wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule is contained in a first vial, and thesecond anticancer agent and the pharmaceutically acceptable carrier arecontained in a second vial, the contents of the first and second vialbeing administered simultaneously or sequentially.
 90. The method ofclaim 83, wherein the solubilizing carrier molecule is awater-solubilizing carrier molecule selected from the group consistingof Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol,Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin oranalogs thereof, and gamma-cyclodextrin or analogs thereof.
 91. Themethod of claim 90, wherein the water-solubilizing carrier molecule isbeta-cyclodextrin.
 92. The method of claim 91, wherein thebeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin.
 93. The method ofclaim 83, wherein the solubilizing carrier molecule is an oil-basedstabilizing carrier molecule.
 94. The method of claim 93, wherein theoil-based solubilizing carrier molecule is lipiodol.
 95. The method ofclaim 87, wherein the concentration of Beta-lapachone in solution is atleast 1 mg/ml.
 96. The method of claim 83, wherein the pharmaceuticalcomposition is administered parenterally.
 97. The method of claim 83,wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptable watersolubilizing carrier molecule, and the anticancer agent and thepharmaceutically acceptable carrier exist as an emulsion.
 98. A methodfor treating cancer comprising administering to a patient apharmaceutical composition comprising a therapeutically effective amountof Beta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable solubilizing carrier molecule, which whendiluted with an aqueous solution for parenteral administration, remainssubstantially soluble in the aqueous solution, and further comprising asecond anticancer agent and a pharmaceutically acceptable carrier. 99.The method of claim 88, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, in the pharmaceuticalcomposition is complexed with the pharmaceutically acceptablesolubilizing carrier molecule, which when diluted with the aqueoussolution for parenteral administration, remains substantially soluble inthe aqueous solution.
 100. The method of claim 98, wherein the secondanticancer agent is a taxane derivative.
 101. The method of claim 100,wherein the taxane derivative is paclitaxel.
 102. The method of claim98, wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule is admixed with the second anticanceragent and the pharmaceutically acceptable carrier and contained in asingle vial.
 103. The method of claim 98, wherein the therapeuticallyeffective amount of Beta-lapachone, or a derivative or analog thereof,and the pharmaceutically acceptable solubilizing carrier molecule iscontained in a first vial, and the second anticancer agent and thepharmaceutically acceptable carrier are contained in a second vial, thecontents of the first and second vial being administered simultaneouslyor sequentially.
 104. The method of claim 98, wherein thepharmaceutically acceptable solubilizing carrier molecule is awater-solubilizing carrier molecule selected from the group consistingof Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol,Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol,Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin oranalogs thereof, and gamma-cyclodextrin or analogs thereof.
 105. Themethod of claim 104, wherein the water-solubilizing carrier molecule isbeta-cyclodextrin.
 106. The method of claim 105, wherein thebeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin.
 107. The method ofclaim 98, wherein the solubilizing carrier molecule is an oil-basedsolubilizing carrier molecule.
 108. The method of claim 107, wherein theoil-based solubilizing carrier molecule is lipiodol.
 109. The method ofclaim 98, wherein the concentration of Beta-lapachone in solution is atleast 1 mg/ml.
 110. The method of claim 98, wherein the pharmaceuticalcomposition comprises a dosage unit in the range between 0.1 mg/kg to 10mg/kg administered from between twice weekly to once every four weeks.111. The method of claim 98, wherein the therapeutically effectiveamount of Beta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable solubilizing carrier molecule, and thesecond anticancer agent and the pharmaceutically acceptable carrierexist as an emulsion.
 112. A method for treating cancer comprisingadministering to a patient a formulation of Beta-lapachone, or aderivative or analog thereof, and a pharmaceutically acceptablesolubilizing carrier molecule, wherein the formulation can befreeze-dried and when subsequently reconstituted in aqueous solution issubstantially soluble, the formulation further comprising a secondanticancer agent and a pharmaceutically acceptable carrier.
 113. Themethod of claim 112, wherein the Beta-lapachone, or a derivative oranalog thereof, in the formulation is complexed with thepharmaceutically acceptable solubilizing carrier.
 114. The method ofclaim 112, wherein the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable, solubilizing carrier molecule is admixedwith the second anticancer agent and the pharmaceutically acceptablecarrier and contained in a single vial.
 115. The method of claim 112,wherein the therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule is contained in a first vial, and thesecond anticancer agent and the pharmaceutically acceptable carrier arecontained in a second vial, the contents of the first and second vialbeing administered simultaneously or sequentially.
 116. The method ofclaim 112, wherein the pharmaceutically acceptable solubilizing carriermolecule is a water-solubilizing carrier molecule selected from thegroup consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80,ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propyleneglycol, Trappsol, alpha-cyclodextrin or analogs thereof,beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin or analogsthereof.
 117. The method of claim 116, wherein the water-solubilizingcarrier molecule is beta-cyclodextrin.
 118. The method of claim 117,wherein the beta-cyclodextrin is hydroxypropyl-beta-cyclodextrin. 119.The method of claim 112, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 120. The method of claim 112, wherein theanticancer agent is a taxane derivative.
 121. The method of claim 120,wherein the taxane derivative is paclitaxel.
 122. The method of claim112, wherein the therapeutically effective amount of Beta-lapachone, ora derivative or analog thereof, and the pharmaceutically acceptablesolubilizing carrier molecule, and the second anticancer agent and thepharmaceutically acceptable carrier exist as an emulsion.
 123. A methodfor treating cancer comprising first administering to a patient apharmaceutical composition comprising a therapeutically effective amountof Beta-lapachone, or a derivative or analog thereof, and a solubilizingcarrier molecule, and subsequently subjecting said patient to radiationtherapy.
 124. The method of claim 123, wherein said pharmaceuticallyacceptable solubilizing carrier molecule is a water-solubilizing carriermolecule selected from the group consisting of Poloxamer, Povidone K17,Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol(PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogsthereof, beta-cyclodextrin or analogs thereof, and gamma-cyclodextrin oranalogs thereof.
 125. The method of claim 124, wherein thewater-solubilizing carrier molecule is beta-cyclodextrin.
 126. Themethod of claim 125, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 127. The method of claim 123, whereinthe solubilizing carrier molecule is an oil-based solubilizing carriermolecule.
 128. The method of claim 127, wherein the oil-basedsolubilizing carrier molecule is lipiodol.
 129. The method of claim 123,wherein the concentration of Beta-lapachone in solution is at least 1mg/ml.
 130. The method of claim 123, wherein said pharmaceuticalcomposition comprises a dosage unit in the range between 0.1 mg/kg to 10mg/kg administered from between twice weekly to once every four weeks.131. The method of claim 123, wherein the therapeutically effectiveamount of Beta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable solubilizing carrier molecule exist as anemulsion.
 132. A pharmaceutical composition comprising a therapeuticallyeffective amount of Beta-lapachone, or a derivative or analog thereof,formulated with a pharmaceutically acceptable fat emulsion vehicle toform an emulsion suitable for parenteral administration.
 133. Thepharmaceutical composition of claim 132, wherein the pharmaceuticallyacceptable fat emulsion vehicle is Intralipid®.
 134. The pharmaceuticalcomposition of claim 132, wherein the concentration of Beta-lapachone inthe emulsion is at least 1 mg/ml.
 135. The pharmaceutical composition ofclaim 132, wherein the emulsion comprises a dosage unit in the rangebetween 0.1 mg/kg to 10 mg/kg administered from between twice weekly toonce every four weeks.
 136. A formulation of Beta-Lapachone, or aderivative or analog thereon, and a pharmaceutically acceptable fatemulsion vehicle, wherein the formulation can be freeze-dried and whensubsequently reconstituted is substantially soluble.
 137. Theformulation of claim 136, wherein the pharmaceutically acceptable fatemulsion vehicle is Intralipid®.
 138. The formulation of claim 136,wherein the concentration of Beta-Lapachone in the formulation is atleast 1 mg/kg.
 139. A pharmaceutical composition comprising atherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, formulated with a pharmaceutically acceptable fatemulsion vehicle to form an emulsion suitable for parenteraladministration, and further comprising a second anticancer agent and apharmaceutically acceptable carrier.
 140. The pharmaceutical compositionof claim 139, wherein the pharmaceutically acceptable fat emulsionvehicle is Intralipid®.
 141. The pharmaceutical composition of claim139, wherein the second anticancer agent is a taxane derivative. 142.The pharmaceutical composition of claim 141, wherein the taxanederivative is paclitaxel.
 143. The pharmaceutical composition f claim139, wherein the concentration of Beta-lapachone in the emulsion is atleast 1 mg/ml.
 144. The pharmaceutical composition of claim 139, whereinthe emulsion comprises a dosage unit in the range between 0.1 mg/kg to10 mg/kg administered from between twice weekly to once every fourweeks.
 145. The pharmaceutical composition of claim 139, wherein theemulsion comprising the therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable fat emulsion vehicle is admixed with thesecond anticancer agent and the pharmaceutically acceptable carrier andcontained in a single vial.
 146. The pharmaceutical composition of claim139, wherein the emulsion comprising the therapeutically effectiveamount of Beta-lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable fat emulsion vehicle is contained in a firstvial, and the second anticancer agent and the pharmaceuticallyacceptable carrier are contained in a second vial.
 147. A kit for thetreatment of a mammalian cancer comprising at least one vial containingBeta-lapachone, or a derivative or analog thereof, according to any oneof claims 132, 136 or
 139. 148. A kit for the treatment of a mammaliantumor comprising one or more vials containing an emulsion comprising atherapeutically effective amount of Beta-lapachone, or a derivative oranalog thereof, and a pharmaceutically acceptable fat emulsion vehicle,and further comprising, within in the same vial or a separate vial, asecond anticancer agent.
 149. The kit of claim 148, wherein thepharmaceutically acceptable fat emulsion vehicle is Intralipid®. 150.The kit of claim 148, wherein the second anticancer agent is a taxariederivative.
 151. The kit of claim 150, wherein the taxane derivative ispaclitaxel
 152. The kit of claim 148, wherein the concentration ofBeta-lapachone in the emulsion is at least 1 mg/ml.
 153. A method fortreating cancer comprising administering to a patient a pharmaceuticalcomposition comprising a therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable fat emulsion vehicle for parenteraladministration.
 154. The method of claim 153, wherein thepharmaceutically acceptable fat emulsion vehicle is Intralipid®. 155.The method of claim 153, wherein the concentration of Beta-lapachone inthe emulsion is at least 1 mg/ml.
 156. The method of claim 153, whereinthe emulsion comprises a dosage unit in the range between 0.1 mg/kg to10 mg/kg Administered from between twice weekly to once every fourweeks.
 157. A method for treating cancer comprising administering to apatient an emulsion comprising a therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, formulated in apharmaceutically acceptable fat emulsion vehicle for parenteraladministration, and further comprising a second anticancer agent and apharmaceutically acceptable carrier.
 158. The method of claim 157,wherein the pharmaceutically acceptable fat emulsion vehicle isIntralipid®.
 159. The method of claim 157, wherein the second anticanceragent is a taxane derivative.
 160. The method of claim 159, wherein thetaxane derivative is paclitaxel.
 161. The method of claim 157, whereinthe concentration of Beta-lapachone in the emulsion is at least 1 mg/ml.162. The method of claim 157, wherein the emulsion comprises a dosageunit in the range between 0.1 mg/kg to 10 mg/kg administered frombetween twice weekly to once every four weeks.
 163. A method fortreating cancer comprising first administering to a patient an emulsioncomprising a therapeutically effective amount of Beta-lapachone, or aderivative or analog thereof, formulated in a pharmaceuticallyacceptable fat emulsion vehicle, and subsequently subjecting the patientto radiation therapy.
 164. The method of claim 163, wherein thepharmaceutically acceptable fat emulsion vehicle is Intralipid®. 165.The method of claim 163, wherein the concentration of Beta-lapachone inthe emulsion is at least 1 mg/ml.
 166. The method of claim 163, whereinthe emulsion comprises a dosage unit in the range between 0.1 mg/kg to10 mg/kg administered from between twice weekly to once every fourweeks.
 167. The method of any one of claims 53, 65, 74, 83, 98, 112,123, 153, 157 or 163, wherein the cancer is characterized by thepresence of one or more solid tumors.
 168. The method of any one ofclaims 53, 65, 74, 83, 98, 112, 123, 153, 157 or 163, wherein the canceris prostate cancer.
 169. The method of any one of claims 53, 65, 74, 83,98, 112, 123, 153, 157 or 163, wherein the cancer is multiple myeloma.170. The method of any one of claims 53, 65, 74, 83, 98, 112, 123, 153,157 or 163, wherein the cancer is a hematologic tumor.
 171. The methodof claim 53, 65, 74, 83, 98, 112, 123, 153, 157 or 163, wherein thecancer is a lymphoid tumor.
 172. The method of any one of claims 53, 65,74, 83, 98, 112, 123, 153, 157 or 163, wherein the cancer is ovariancancer.
 173. The method of any one of claims 53, 65, 74, 83, 98, 112,123, 153, 157 or 163, wherein the cancer is breast cancer.
 174. Asterile injectable pharmaceutical composition for intravenousadministration comprising a complex of a therapeutically effectiveamount of Beta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable water-solubilizing carrier molecule. 175.The sterile injectable pharmaceutical composition of claim 174, whereinthe composition is in aqueous solution.
 176. The sterile injectablepharmaceutical composition of claim 174, wherein the pharmaceuticallyacceptable, water solubilizing carrier molecule ishydroxypropyl-beta-cyclodextrin.
 177. The sterile injectablepharmaceutical composition of claim 174, further comprising a secondanticancer agent and a pharmaceutically acceptable carrier.
 178. Thesterile injectable pharmaceutical composition of claim 177, wherein thesecond anticancer agent is a taxane derivative.
 179. The sterileinjectable pharmaceutical composition of claim 178, wherein the taxanederivative is paclitaxel.
 180. The sterile injectable pharmaceuticalcomposition of claim 174, wherein the concentration of Beta-lapachone insolution is at least 1 mg/ml.
 181. The sterile injectable pharmaceuticalcomposition of claim 174, wherein said pharmaceutical compositioncomprises a dosage unit in the range between 0.1 mg/kg to 10 mg/kgadministered from between twice weekly to once every four weeks. 182.The sterile injectable pharmaceutical composition of claim 174, whereinthe therapeutically effective amount of Beta-lapachone, or a derivativeor analog thereof, and the pharmaceutically acceptable watersolubilizing carrier molecule exist as an emulsion.
 183. A sterileinjectable pharmaceutical composition for intravenous administrationcomprising a complex of a therapeutically effective amount ofBeta-lapachone, or a derivative or analog thereof, and apharmaceutically acceptable oil-based solubilizing carrier molecule.184. The sterile injectable pharmaceutical composition of claim 183,wherein the pharmaceutically acceptable, oil-based solubilizing carriermolecule is lipiodol.
 185. The sterile injectable pharmaceuticalcomposition of claim 183, further comprising a second anticancer agentand a pharmaceutically acceptable carrier.
 186. The sterile injectablepharmaceutical composition of claim 185, wherein the second anticanceragent is a taxane derivative.
 187. The sterile injectable pharmaceuticalcomposition of claim 186, wherein the taxane derivative is paclitaxel.188. The sterile injectable pharmaceutical composition of claim 183,wherein the concentration of Beta-lapachone in solution is at least 1mg/ml.
 189. The sterile injectable pharmaceutical composition of claim183, wherein said pharmaceutical composition comprises a dosage unit inthe range between 0.1 mg/kg to 10 mg/kg administered from between twiceweekly to once every four weeks.
 190. The sterile injectablepharmaceutical composition of claim 183, wherein the therapeuticallyeffective amount of Beta-lapachone, or a derivative or analog thereof,and the pharmaceutically acceptable water solubilizing carrier moleculeexist as an emulsion.
 191. A sterile injectable pharmaceuticalcomposition for intravenous administration comprising a therapeuticallyeffective amount of Beta-lapachone, or a derivative or analog thereof,in a pharmaceutically acceptable fat emulsion vehicle.
 192. The sterileinjectable pharmaceutical composition of claim 191, wherein the fatemulsion is Intralipid®.
 193. The sterile injectable pharmaceuticalcomposition of claim 191, further comprising an anticancer agent and apharmaceutically acceptable carrier.
 194. The sterile injectablepharmaceutical composition of claim 191, wherein the anticancer agent isa taxane derivative.
 195. The sterile injectable pharmaceuticalcomposition of claim 194, wherein the taxane derivative is paclitaxel.196. The sterile injectable pharmaceutical composition of claim 191,wherein the concentration of Beta-lapachone in the emulsion is at least1 mg/ml.
 197. The sterile injectable pharmaceutical composition of claim191, wherein the pharmaceutical composition comprises a dosage unit inthe range between 0.1 mg/kg to 10 mg/kg administered from between twiceweekly to once every four weeks.
 198. A topical composition for treatinga dermatologic condition in a subject comprising a therapeuticallyeffective amount of a Beta-Lapachone, or a derivative or analog thereofand a pharmaceutically acceptable solubilizing carrier molecule whereinsaid composition is topically applied to said subject to treat saiddermatologic condition.
 199. The topical composition of claim 198,wherein the composition is an aqueous solution or an oil solution. 200.The topical composition of claim 198, wherein the pharmaceuticallyacceptable solubilizing carrier molecule is a water-solubilizing carriermolecule.
 201. The topical composition of claim 198, wherein thepharmaceutically acceptable solubilizing carrier molecule is anoil-based solubilizing carrier molecule.
 202. The topical composition ofclaim 198, wherein the therapeutically effective amount ofBeta-Lapachone, or a derivative or analog thereof, and thepharmaceutically acceptable solubilizing carrier molecule exist as anemulsion.
 203. The topical composition of claim 198, wherein thedermatological condition includes basal-cell carcinoma, squamous-cellcancer, Kaposi's sarcoma and melanoma.
 204. The topical composition ofclaim 198, wherein the dermatological condition is psoriasis.
 205. Amethod for treating skin cancer comprising administering to a patient atherapeutically effective amount of the pharmaceutical composition ofclaim
 198. 206. The method of claim 205, wherein the pharmaceuticalcomposition is administered topically.
 207. A method for treating adermatologic condition comprising administering to a patient atherapeutically effective amount of the pharmaceutical composition ofclaim
 198. 208. The method for claim 207, wherein the dermatologiccondition is psoriasis.
 209. The method of claim 207, wherein thepharmaceutical composition is administered topically.
 210. Apharmaceutical composition comprising a therapeutically effective amountof Beta-Lapachone or a derivative or analog thereof, formulated with apharmaceutically acceptable fat emulsion vehicle suitable for topicaladministration.
 211. A method for treating skin cancer comprisingadministering to a patient a therapeutically effective amount of apharmaceutical composition of claim
 210. 212. A method for treating adermatologic condition comprising administering to a patient atherapeutically effective amount of the pharmaceutical composition ofclaim
 210. 213. The method for claim 212, wherein the dermatologiccondition is psoriasis.
 214. A compound having the formula:


215. A method of treating cancer comprising administering to a patient apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 214 and a solubilizing carrier molecule.
 216. Amethod of treating a dermatologic condition comprising administering toa patient a pharmaceutical composition comprising a therapeuticallyeffective amount of the compound of claim 214 and a solubilizing carriermolecule.
 217. The method for claim 216, wherein the dermatologiccondition is psoriasis.
 218. A method of treating cancer comprisingadministering to a patient a pharmaceutical composition comprising atherapeutically effective amount of 4-acetoxy-Beta-Lapachone and asolubilizing carrier molecule.
 219. A method of treating cancercomprising administering to a patient a pharmaceutical compositioncomprising a therapeutically effective amount of4-acetoxy-3-bromo-Beta-Lapachone and a solubilizing carrier molecule.220. A method of treating cancer comprising administering to a patient apharmaceutical composition comprising a therapeutically effective amountof 2-ethyl-6-hydroxynaphtho[2,3-b]furan-4,5-dione and a solubilizingcarrier molecule.
 221. A method of treating a dermatologic conditioncomprising administering to a patient a pharmaceutical compositioncomprising a therapeutically effective amount of4-acetoxy-Beta-Lapachone and a solubilizing carrier molecule.
 222. Themethod for claim 221, wherein the dermatologic condition is psoriasis.223. A method of treating a dermatologic condition comprisingadministering to a patient a pharmaceutical composition comprising atherapeutically effective amount of 4-acetoxy-3-bromo-Beta-Lapachone anda solubilizing carrier molecule.
 224. The method for claim 223, whereinthe dermatologic condition is psoriasis.
 225. A method of treating adermatologic condition comprising administering to a patient apharmaceutical composition comprising a therapeutically effective amountof 2-ethyl-6-hydroxynaphtho[2,3-b]furan-4,5-dione and a solubilizingcarrier molecule.
 226. The method for claim 225, wherein thedermatologic condition is psoriasis.